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. The chemokine monokine induced by interferon-γ (Mig) is involved in the recruitment of inflammatory cells and liver injury during hepatitis B virus (HBV) infection. HBV protein X contributes to Mig expression in vitro by activation of nuclear factor (NF)-κB; however, the molecular mechanisms by which HBV induces Mig expression in vivo are unknown. In this paper, we established a mouse model for HBV study by tail vein injection of HBV genome-containing adenovirus vectors. Host immune response to the secreted hepatitis B surface antigen and e antigen was detected and serum alanine aminotransferase (ALT) was elevated at different time points. We also demonstrated that peripheral and intrahepatic Mig expression was increased after Ad-HBV infection. This was followed by inflammatory cell migration and formation of inflammatory foci in the liver. In addition, NF-κB p65 subunit translocated from the cytoplasm to the nucleus, and phosphoinositide 3-kinase/Akt, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were to some extent phosphorylated after HBV injection. Following tail vein injection of Mig siRNA/ in vivo-jetPEI-Gal complex, Mig expression was partially suppressed, inflammatory cell migration was inhibited, serum level of ALT were reduced. In conclusion, through NF-κB activation, HBV induced Mig expression in vivo, which recruited peripheral inflammatory cells to the liver and resulted in liver damage. Phosphorylation of phosphoinositide 3-kinase/Akt, ERK and JNK but not p38 might involved in the molecular mechanisms underlying HBV induced Mig expression in vivo. [ABSTRACT FROM AUTHOR]

The effects of human immunoglobulin preparations for intravenous use (IVIg) on in vitro-induced monokine production were studied. Individual peripheral blood monocytes, obtained from healthy blood donors, which produced interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) after in vitro stimulation, were identified by cytokine-specific monoclonal antibodies (mAb) and indirect immunofluorescence technique. Lipopylosaccharide (LPS) or Borrelia burgdorferi spirochetes (Bb) were used to induce TNF-α and IL-6 production in cultures. Peak synthesis occurred 2.5 hr after initiation of the cultures in tile majority of the monocytes, but not aL all in lymphocytes. The monocytes were identified by two-colour staining using a monocyte-specific mAb. IL-6 was produced by 64 ± 8% or 71 ± 9% (means±SD) of the non-IVIg-exposed monocytes after LPS or Bb stimulation, respectively (n = 12). A dose-dependent and significant reduction of the number of IL-6 producing cells was noted in the IVIg-supplemented cultures (P < 0.003). In these cultures 24 ± 12% or 29 ± 12% of the monocytes made IL-6 in response to LPS or Bb. Kinetic studies indicated a sustained significant inhibition of IL-6 production during 24 hr of culture (P < 0.001). In contrast, TNF-α synthesis was not inhibited by IVIg. LPS or Bb stimulation resulted in 47 ± 18% or 69 ± 7% TNF-α producing cells versus 48 ± 9% or 59 ± 8% in IVIg-supplemented cultures. These results indicate down-regulation of IL-6, but not TNF-α production, by IVIg. A direct antigen neutralization is an unlikely explanation for the divergent effects observed on monokine production after IVIg addition. [ABSTRACT FROM AUTHOR]

Background: T-helper (Th) 2 cytokines are thought to mediate most of the allergic inflammatory responses associated with atopic asthma. But the Th1-related chemokine, interferon-inducible protein 10 (IP-10)/CXCL10, was the predominant chemokine measured during human allergic pulmonary late-phase reaction. The aim of the present study was to evaluate the role of Th1- and Th2- related chemokines in the pathogenesis of asthma exacerbation. Methods: Plasma levels of the Th2-related C-C chemokine I-309 (CCL1), the Th1-related CXC chemokines IP-10, and the monokine induced by interferon-γ (Mig)/CXCL9 were measured in patients with stable asthma. Results: These results were compared to the results measured prior to, and after corticosteroid treatment, in patients who experienced asthma exacerbations. A significant increase in the plasma levels of IP-10 and Mig, but not I-309, were found in patients with an acute exacerbation in contrast to patients with stable asthma. Plasma levels of IP-10 and Mig were significantly higher in patients during an acute asthma exacerbation than during a subsequent convalescent period. Conclusions: The Th1-related CXC chemokines IP-10 and Mig may be useful inflammatory markers of asthma exacerbation in children. [ABSTRACT FROM AUTHOR]

Background: Host inflammatory and immune responses play an important role in aggressive periodontitis (AgP). Thus, this study aims to evaluate levels of the innate immunity-related markers calprotectin, colony-stimulating factor (CSF)-1, macrophage migration inhibitory factor (MIF), monokine induced by interferon-γ (MIG), and matrix metalloproteinase (MMP)-8 in serum and saliva from patients with generalized AgP and those with gingivitis or a healthy periodontium.Methods: This study enrolled 40 individuals (17 males and 23 females; mean age 33.30 ± 9.31 years), 15 with generalized AgP, 15 with gingivitis, and 10 who were periodontally healthy. Full-mouth periodontal examinations were performed, and serum and saliva were collected. Levels of calprotectin, CSF-1, MIF, MIG, and MMP-8 were measured using enzyme-linked immunosorbent assays.Results: In serum, mean levels of calprotectin were 2.06-fold higher in patients with AgP than in healthy patients (P = 0.01). Serum levels of MMP-8 were significantly elevated in patients with AgP compared with both healthy patients and those with gingivitis, by 2.60-fold and 2.77-fold, respectively (P = 0.03 and P = 0.009, respectively). In saliva, levels of MMP-8 were 5.66-fold higher in patients with AgP than in healthy patients (P = 0.02). CSF-1, MIF, and MIG levels in both serum and saliva did not differ significantly among the groups.Conclusions: Serum levels of calprotectin and MMP-8 are elevated in patients with AgP. MMP-8 levels are also increased in saliva from patients with AgP. These results support involvement of innate immune response in the pathogenesis of AgP. [ABSTRACT FROM AUTHOR]

The effect of cinnamon (Cinnamomum zeylanicum) bark essential oil (CBEO) on human skin cells has not been elucidated. Therefore, we investigated the activity of a commercially available CBEO in a validated human dermal fibroblast system, a model of chronic inflammation and fibrosis. We first evaluated the impact of CBEO on 17 protein biomarkers that play critical roles in inflammation and tissue remodeling. The impact of CBEO on genome-wide gene expression was also evaluated. CBEO showed strong anti-proliferative effects on skin cells and significantly inhibited the production of several inflammatory biomarkers, including vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, monocyte chemoattractant protein-1, interferon gamma-induced protein 10, interferon-inducible T-cell alpha chemoattractant, and monokine induced by gamma interferon. In addition, CBEO significantly inhibited the production of several tissue remodeling molecules, including epidermal growth factor receptor, matrix metalloproteinase-1, and plasminogen activator inhibitor-1. Macrophage colony-stimulating factor, which is an immunomodulatory protein molecule, was also significantly inhibited by CBEO. Furthermore, CBEO significantly modulated global gene expression and altered signaling pathways, many of which are important in inflammation, tissue remodeling, and cancer biology. The study shows that CBEO is a promising antiinflammatory agent; however, further research is required to clarify its clinical efficacy. © 2017 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objectives The aim of the study was to assess the impact of rapid and sustained viral control produced by combination antiretroviral therapy (c ART) on HIV-associated immune activation and inflammation. Methods In this longitudinal observational study, we examined changes in interleukin-6 ( IL-6), interferon-γ-inducible protein-10 ( IP-10), monokine induced by interferon-γ ( MIG) and soluble CD14 (s CD14) levels during 2 years of effective first-line c ART. Biomarker levels before and after c ART were compared with those observed in healthy subjects, using the Wilcoxon signed rank test. Elevated biomarker levels were defined with respect to values for healthy subject (mean + 2 standard deviations). Factors associated with persistently elevated biomarker levels after 2 years of c ART were identified by logistic regression. Results We included in the study 139 patients with a median HIV-1 RNA level of 4.8 log10 HIV-1 RNA copies/mL and a median CD4 cell count of 294 cells/μL at c ART initiation [day 0 ( D0)]. At D0, all biomarker levels were higher than in healthy subjects ( P < 0.05). After 2 years of c ART, IL-6, IP-10 and MIG levels fell significantly, by a median of 0.54, 420 and 1107 pg/mL, respectively (all P < 0.001), and were no longer elevated in > 75% of patients. In contrast, s CD14 levels did not change significantly (0.18 × 106 pg/mL; P = 0.102) and remained elevated. Older age was associated with elevated levels of IP-10 [odds ratio ( OR) 1.60 per 10 years older; P = 0.047] and MIG ( OR 1.92 per 10 years older; P = 0.007) after 2 years of c ART. Conclusions The rapid and sustained viral suppression produced by first-line c ART reduced IL-6, IP-10 and MIG to normal levels, while s CD14, a marker of monocyte activation, remained elevated. High levels of IP-10 and MIG tended to persist in older patients. [ABSTRACT FROM AUTHOR]

Objective: To test the hypotheses that obesity due to a very high-fat diet induces knee osteoarthritis (OA), and that short-term wheel-running exercise protects against obesity-induced knee OA by reducing systemic inflammation and metabolic dysregulation., Methods: Male C57BL/6J mice were fed either a control diet (13.5% kcal from fat) or a very high-fat diet (60% kcal from fat) from age 12 weeks to age 24 weeks. From 20 to 24 weeks of age, half of the mice were housed with running wheels. The severity of knee OA was determined by assessing histopathologic features, and serum cytokines were measured using a multiplex bead immunoassay and enzyme-linked immunosorbent assays. Body composition was quantified by dual-energy x-ray absorptiometry, and insulin resistance was assessed by glucose tolerance testing., Results: Feeding mice with a very high-fat diet increased knee OA scores and levels of serum leptin, adiponectin, KC (mouse analog of interleukin-8 [IL-8]), monokine induced by interferon-γ (CXCL9), and IL-1 receptor antagonist to an extent in proportion to the gain in body fat (3-fold increase in percent body fat compared to controls). Wheel-running exercise reduced progression of OA in the medial femur of obese mice. In addition, exercise disrupted the clustering of cytokine expression and improved glucose tolerance, without reducing body fat or cytokine levels., Conclusion: Obesity induced by a very high-fat diet in mice causes OA and systemic inflammation in proportion to body fat. Increased joint loading is not sufficient to explain the increased incidence of knee OA with obesity, as wheel running is protective rather than damaging. Exercise improves glucose tolerance and disrupts the coexpression of proinflammatory cytokines, suggesting that increased aerobic exercise may act independently of weight loss in promoting joint health., (Copyright © 2012 by the American College of Rheumatology.)

Comorbidities that involve infectious and noninfectious diseases, such as malaria and cancer, have been described. Cancer and malaria induce changes in the nociceptive and inflammatory responses through similar pathophysiological mechanisms. However, it is unclear whether malaria and antimalarial treatment can change the inflammatory and nociceptive responses induced by solid cancer. Therefore, the present study experimentally evaluated the effect of infection by Plasmodium berghei strain ANKA and chloroquine treatment on the nociceptive and inflammatory responses induced by the solid Ehrlich tumor in male BALB/c mice. On the 1st experimental day, mice were infected with Plasmodium berghei and injected with tumor cells in the left hind paw. From the 7th to the 9th experimental day, mice were treated daily with chloroquine. The parasitemia was evaluated on the 7th and 10th days after infection. On the 11th experimental day, mice were evaluated on the von Frey filament test, the hot plate test, and the paw volume test. At the end of the experimental tests on the 11th day, the peripheral blood of all mice was collected for dosing of IL-1β and TNF-α. The blood parasitemia significantly increased from the 7th to the 10th day. The chloroquine treatment significantly decreased the parasitemia on the 10th day. The presence of the tumor did not significantly change the parasitemia on the 7th and 10th days in mice treated and nontreated with chloroquine. On the 11th day, the mechanical and thermal nociceptive responses significantly increased in mice with tumors. The treatment with antimalarial significantly reduced the mechanical nociceptive response induced by tumors. The hyperalgesia induced by tumors did not change with malaria. The mechanical and thermal hyperalgesia induced by the tumor was significantly reduced in mice treated and healed from malaria. On the 11th day, the volume of the paw injected by the tumor was significantly increased. The mice treated with chloroquine, infected with malaria, or healed of malaria showed reduced paw edema induced by the tumor. Mice with tumors did not show a change in IL-β and TNF-α serum levels. Mice with tumors showed a significant increase in serum levels of IL-1β but not TNF-α when treated with chloroquine, infected with malaria, or healed of malaria. In conclusion, the results show that malaria infection and chloroquine treatment can influence, in synergic form, the nociceptive and inflammatory responses induced by the solid tumor. Moreover, the mechanical antinociception, the thermal hyperalgesia, and the antiedema effect observed in mice treated with chloroquine and healed from malaria can be related to the increase in the serum level of IL-1β. [ABSTRACT FROM AUTHOR]

Background: Allergic asthma is an important respiratory system problem characterized by airway inflammation, breathlessness, and bronchoconstriction. Allergic asthma and its outcomes are triggered by type 2 allergic immune responses. Tectorigenin is a methoxy‐isoflavone with anti‐inflammatory effects. In this study, we investigated the effects of tectorigenin on the pathophysiology of allergic asthma in an animal model. Methods: Asthmatic mice were treated with tectorigenin. Then airway hyperresponsiveness (AHR), eosinophil percentage, levels of interleukin (IL)‐33, IL‐25, IL‐13, IL‐5, IL‐4, total and ovalbumin (OVA)‐specific immunoglobulin (Ig)E, and lung histopathology were evaluated. Result: Tectorigenin significantly (P 〈 0.05) reduced eosinophil infiltration (41 ± 7%) in the broncho‐alveolar lavage fluid (BALF), serum IL‐5 level (41 ± 5, pg/mL), and bronchial and vascular inflammation (scores of 1.3 ± 0.2 and 1.1 ± 0.3, respectively) but had no significant effects on AHR, serum levels of IL‐33, −25, −13, and −4 (403 ± 24, 56 ± 7, 154 ± 11, and 89 ± 6 pg/mL, respectively), total and OVA‐specific IgE (2684 ± 265 and 264 ± 19 ng/mL, respectively), goblet cell hyperplasia, and mucus production. Conclusion: Tectorigenin could control inflammation and the secretion of inflammatory mediators of asthma, so it can be regarded as a potential antiasthma treatment with the ability to control eosinophilia‐related problems. [ABSTRACT FROM AUTHOR]

Objective: To study the expression levels and immunostimulatory capacities of interleukin-7 (IL-7) in primary Sjögren's syndrome., Methods: Labial salivary gland (LSG) IL-7 expression was determined by immunohistochemistry, using a quantitative scoring system, in 30 patients with sicca syndrome: 15 patients with primary Sjögren's syndrome (SS) and 15 patients with non-SS sicca syndrome. The correlation of IL-7 expression in LSGs with parameters of local and peripheral disease was studied, and serum and salivary IL-7 levels were determined. Additionally, the effects of IL-7 on cytokine production by peripheral blood mononuclear cells (PBMCs) from patients with primary SS were determined in vitro by Luminex multicytokine assay and compared with the effects in control subjects., Results: The expression of IL-7 in LSGs was higher in patients with primary SS compared with that in patients with non-SS sicca syndrome. IL-7 was observed primarily in the vicinity of lymphocytic infiltrates. Salivary IL-7 levels in patients with primary SS were higher than those in control subjects. In all 30 patients with sicca syndrome, IL-7 expression in LSGs correlated with parameters of both local and peripheral disease. Furthermore, IL-7 stimulated T cell-attracting and T cell-differentiating cytokines (monokine induced by interferon-gamma [IFNgamma], IFNgamma-inducible 10-kd protein, IL-12, and IL-15), as well as Th1 (IFNgamma), Th2 (IL-4), Th17 (IL-17A), proinflammatory (tumor necrosis factor alpha and IL-1alpha), and regulatory (IL-10 and IL-13) cytokine production by PBMCs. All of these cytokines were previously shown to be associated with primary SS. The IL-7-induced increase in IL-10 production in patients with primary SS was reduced compared with that in control subjects., Conclusion: The correlation between LSG IL-7 expression and (local) disease parameters in primary SS as well as the IL-7-mediated induction of inflammatory cytokines indicate that IL-7 might contribute to the immunopathology of primary SS.

We investigated changes in a large battery of pro- and anti-inflammatory cytokines in elite female soccer players following two 90-min games separated by a 72-h active or passive recovery. Blood samples were taken from 10 players before, within 15–20 min, 21, 45 and 69 h after the first game and within 15–20 min after the second game. The leukocyte count was analyzed, together with several plasma pro- and anti-inflammatory cytokines, using a multiplex bead array system. After the first and second game, the total leukocytes and neutrophils increased significantly. Likewise, increases ( P<0.05) in pro-inflammatory cytokines [interleukin (IL)-12, tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), IL-17], chemokines [monocyte chemotactic protein-1 (MCP-1), IL-8 and monokine induced by gamma interferon (MIG)], anti-inflammatory cytokines (IL-2R, IL-4, IL-5, IL-7, IL-10, IL-13, INF-α) and the mixed cytokine IL-6 were observed. Leukocyte and cytokine levels were normalized within 21 h. Active recovery (low-intensity exercises) did not affect the cytokine responses. A dampened cytokine response was observed after the second game as only IL-12, IL-6, MCP-1, IL-8 and MIG increased ( P<0.05). In conclusion, a robust pro- and anti-inflammatory cytokine response occurs after the first but not the second soccer game. The implications of the dampened cytokine response in female players after the second game are unknown. [ABSTRACT FROM AUTHOR]

M. Müller, S. Carter, M. J. Hofer and I. L. Campbell (2010) Neuropathology and Applied Neurobiology 36, 368–387 The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity – a tale of conflict and conundrum The chemokines CXCL9, CXCL10 and CXCL11 (also known as monokine induced by interferon-γ, interferon-inducible protein-10 and interferon-inducible T cell α-chemoattractant, respectively) are structurally and functionally related molecules within the non-ELR CXC chemokine subgroup. These chemokines are generally not detectable in most non-lymphoid tissues under physiological conditions but are strongly induced by cytokines, particularly interferon-γ, during infection, injury or immunoinflammatory responses. CXCL9, CXCL10 and CXCL11 each bind to a common primary receptor, CXCR3, and possibly to additional receptors. They are best known for their role in leucocyte trafficking, principally acting on activated CD4+ Th1 cells, CD8+ T cells and NK cells. An abundance of data demonstrates that CXCL9, CXCL10 and CXCL11 are produced in many diverse pathologic conditions of the central nervous system. More recent attention has focussed on the function of these chemokines in the central nervous system inflammation. The results of these studies have proven to be sometimes surprising and other times contradictory. Here we discuss the likely more subtle and perhaps divergent roles for these chemokines in the pathogenesis of neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]

During neuronal-induced inflammation, mast cells may respond to stimuli such as neuropeptides in an FcεRI-independent manner. In this study, we characterized human mast cell responses to substance P (SP), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) and compared these responses to human mast cell responses to immunoglobulin E (IgE)/anti-IgE and compound 48/80. Primary cultured mast cells, generated from CD34+ progenitors in the presence of stem cell factor and interleukin-6 (IL-6), and human cultured mast cells (LAD2) were stimulated with these and other stimuli (gastrin, concanavalin A, radiocontrast media, and mannitol) and their degranulation and chemokine production was assessed. VIP and SP stimulated primary human mast cells and LAD cells to degranulate; gastrin, concanavalin A, radiocontrast media, mannitol, CGRP and NGF did not activate degranulation. While anti-IgE stimulation did not induce significant production of chemokines, stimulation with VIP, SP or compound 48/80 potently induced production of monocyte chemoattractant protein-1, inducible protein-10, monokine induced by interferon-γ (MIG), RANTES (regulated on activation, normal, T-cell expressed, and secreted) and IL-8. VIP, SP and compound 48/80 also activated release of tumour necrosis factor, IL-3 and granulocyte–macrophage colony-stimulating factor, but not IL-4, interferon-γ or eotaxin. Human mast cells expressed surface neurokinin 1 receptor (NK1R), NK2R, NK3R and VIP receptor type 2 (VPAC2) but not VPAC1 and activation of human mast cells by IgE/anti-IgE up-regulated expression of VPAC2, NK2R, and NK3R. These studies demonstrate the pattern of receptor expression and activation of mast cell by a host of G-protein coupled receptor ligands and suggest that SP and VIP activate a unique signalling pathway in human mast cells. These results are likely to have direct relevance to neuronally induced inflammatory diseases. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) is a leading cause of chronic liver disease that can progress to cirrhosis and/or hepatocellular carcinoma. Intrahepatic inflammation and liver cell injury are defining features of chronic HCV infection. Chemokines, chemotactic cytokines that attract leucocytes to inflammatory sites, may be important in the development of intrahepatic inflammation. As T-helper (Th)1 inflammatory cells, characterized by interferon (IFN)- γ and interleukin (IL)-2 secretion, predominate in the liver during chronic HCV infection, chemokines that attract these cells might be particularly important in disease progression. In this review, we focus on the role of Th1 chemokines, which are all members of the CXC or CC subfamilies. Among the CXC chemokines, the non-ELR group comprised of IFN- γ-inducible protein 10 (IP-10), monokine induced by IFN- γ (Mig) and IFN-inducible T-cell- α chemoattractant (I-TAC), attract Th1 cells through the interaction with their receptor, CXCR3. Among the CC subfamily, Th1-associated chemokines include regulated upon activation, normal T-cell expressed and secreted (RANTES) and macrophage inflammatory proteins (MIP)1 α and β. These chemokines attract cells through an interaction with their receptor, CCR5. While peripheral blood and intrahepatic levels of all of these chemokines are elevated in chronic hepatitis C patients, only select chemokines have been found to be correlated with hepatic inflammation. Among the six chemokines, IP-10 has uniquely been shown to have prognostic utility as a marker of treatment outcome. In the future, chemokines might be used to monitor the natural course and progression of HCV-associated liver disease, to identify patients with a high likelihood of achieving a therapeutic response, and they may even have potential as therapeutic targets. [ABSTRACT FROM AUTHOR]

Ketotifen is a mast cell stabilizer and useful in younger children with allergic diseases such as asthma and allergic rhinitis. Macrophage-derived chemokine (MDC) is a T-helper cell type 2 (Th2)-related chemokine involved in recruitment of Th2 cells toward allergen-challenged inflammation. However, the Th1-related chemokines, interferon-inducible protein 10 (IP-10) /CXCL10, and the monokine induced by interferon-gamma (MIG)/CXCL9 are also important in allergen-induced asthma in animal models. We investigated the effects of ketotifen on the expression of Th1- and Th2-related chemokines of human monocytes in vitro and ex vivo. Ketotifen (5–50 μm) significantly down-regulated lipopolysaccharide (LPS)-induced MDC, MIG and IP-10 (p < 0.05, each comparison) in THP-1 cells and human primary monocytes in a dose-dependent manner. SB203580 [p38-mitogen-activated protein kinase (MAPK) inhibitor] suppressed LPS-induced MDC and IP-10 expression, and PD98059 (ERK–MAPK inhibitor) could only suppress LPS-induced IP-10, but not MDC expression. LPS-induced pp38 and p-ERK expression of THP-1 monocytic cells was suppressed by ketotifen. These data demonstrate that ketotifen is effective in down-regulating LPS-induced MDC, MIG and IP-10, which play important roles in the pathogenesis of airway inflammation. The suppressive effect on MDC and IP-10 may, at least in part, involve the down-regulation of LPS-induced p38 and ERK–MAPK expression. [ABSTRACT FROM AUTHOR]

Background: High throughput technologies provide new opportunities to further investigate the pathophysiology of ischemic strokes. The present cross‐sectional study aimed to evaluate potential associations between the etiologic subtypes of ischemic stroke and blood‐based proteins. Methods: We investigated the associations between ischemic stroke subtypes and a panel of circulating inflammation biomarkers in 364 patients included in the Stroke Cohort Augsburg (SCHANA). Stroke etiologies were categorized according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Serum concentrations of 52 biomarkers were measured using the Bio‐Plex Pro™ Human Cytokine Screening Panel, ICAM‐1 set and VCAM‐1 set, plus the Pro™ Human TH17 cytokine sCD40L set and IL31 set (all Bio‐Rad, USA). Multivariable linear regression models were used to examine associations. Point estimates were calculated as the mean difference in σ‐standardized cytokine levels on the log2‐scale. Results: Stromal‐cell‐derived‐factor 1 alpha (SDF‐1a) showed significantly higher serum levels in cardioembolic compared with large vessel atherosclerotic stroke (β = 0.48; 95% CI 0.22; 0.75; Padj = 0.036). Significantly lower levels of interleukin‐6 (IL‐6) (β = −0.53; 95% CI −0.84; −0.23; Padj = 0.036) and macrophage migration inhibitory factor (MIF) (β = −0.52; 95% CI −0.84; −0.21; Padj = 0.043) were found in the small vessel versus large vessel stroke subtype. Conclusions: Immune dysregulations observed in different stroke subtypes might help uncover pathophysiological mechanisms of the disease. Further studies are needed to validate identified biomarkers in diverse study populations before they can potentially be used in clinical practice to further improve stroke management and patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Periradicular tissue fluid (PTF) offers a source of diagnostic, prognostic and predictive biomarkers for endodontic disease. Aims: (1) To optimize basic parameters for PTF paper point sampling in vitro for subsequent in vivo application. (2) To compare proteomes of PTF from teeth with normal apical tissues (NAT) and asymptomatic apical periodontitis (AAP) using high‐throughput panels. Methodology: (1) To assess volume absorbance, paper points (n = 20) of multiple brands, sizes and sampling durations were inserted into PBS/1%BSA at several depths. Wetted lengths (mm) were measured against standard curves to determine volume absorbance (μL). To assess analyte recovery, paper points (n = 6) loaded with 2 μL recombinant IL‐1β (15.6 ng/mL) were eluted into 250 μL: (i) PBS; (ii) PBS/1% BSA; (iii) PBS/0.1% Tween20; (iv) PBS/0.25 M NaCl. These then underwent: (i) vortexing; (ii) vortexing/centrifugation; (iii) centrifugation; (iv) incubation/vortexing/centrifugation. Sandwich‐ELISAs determined analyte recovery (%) against positive controls. (2) Using optimized protocols, PTF was retrieved from permanent teeth with NAT or AAP after accessing root canals. Samples, normalized to total fluid volume (TFV), were analysed to determine proteomic profiles (pg/TFV) of NAT and AAP via O‐link Target‐48 panel. Correlations between AAP and diagnostic accuracy were explored using principal‐component analysis (PCA) and area under receive‐operating‐characteristic curves (AUC [95% CI]), respectively. Statistical comparisons were made using Mann–Whitney U, anova and post hoc Bonferonni tests (α <.01). Results: (1) UnoDent's 'Classic' points facilitated maximum volume absorbance (p <.05), with no significant differences after 60 s (1.6 μL [1.30–1.73]), 1 mm depth and up to 40/0.02 (2.2 μL [1.98–2.20]). For elution, vortexing (89.3%) and PBS/1% BSA (86.9%) yielded the largest IL‐1β recovery (p <.05). (2) 41 (NAT: 13; AAP: 31) PTF samples proceeded to analysis. The panel detected 18 analytes (CCL‐2, ‐3, ‐4; CSF‐1; CXCL‐8, ‐9; HGF; IL‐1β, ‐6, ‐17A, ‐18; MMP‐1, ‐12; OLR‐1; OSM; TNFSF‐10, ‐12; VEGF‐A) in ≥75% of AAP samples at statistically higher concentrations (p <.01). CXCL‐8, IL‐1β, OLR‐1, OSM and TNFSF‐12 were strongly correlated to AAP. 'Excellent' diagnostic performance was observed for TNFSF‐12 (AUC: 0.94 [95% CI: 0.86–1.00]) and the PCA‐derived cluster (AUC: 0.96 [95% CI: 0.89–1.00]). Conclusions: Optimized PTF sampling parameters were identified in this study. When applied clinically, high‐throughput proteomic analyses revealed complex interconnected networks of potential biomarkers. TNFSF‐12 discriminated periradicular disease from health the greatest; however, clustering analytes further improved diagnostic accuracy. Additional independent investigations are required to validate these findings. [ABSTRACT FROM AUTHOR]

Measurement of the health and disease status of free‐ranging primates is often limited by a lack of available biomarkers of immune activation and inflammation that can be applied noninvasively via the measurement of urine or fecal samples. Here, we evaluate the potential usefulness of noninvasive urinary measurements of a number of cytokines, chemokines, and other markers of inflammation and infection. We took advantage of surgery‐associated inflammation in seven captive rhesus macaques, collecting urine samples before and after the medical interventions. We measured these urine samples for 33 different markers of inflammation and immune activation that are known to be responsive to inflammation and infection in rhesus macaque blood samples, via the Luminex platform. We also measured all samples for concentrations of the soluble urokinase plasminogen activator receptor (suPAR), which we had validated in a prior study as an effective biomarker of inflammation. Despite urine samples being collected in captivity under ideal conditions (clean, no contamination with feces or soil, frozen quickly), 13/33 biomarkers measured via Luminex were found at concentrations below detection limits in >50% of samples. Of the remaining 20 markers, only 2 showed significant increases in response to surgery—IL18 and MPO (myeloperoxidase). However, suPAR measurements of the same samples show a consistent marked increase in response to surgery that is absent from the patterns of IL18 and MPO measurement. Given that our samples were collected under conditions that are greatly preferable to those usually encountered in the field, urinary cytokine measurements via the Luminex platform seem overall unpromising for primate field studies. Research Highlights: 13/33 cytokines validated for measurement in rhesus macaque plasma were measured below minimum assay sensitivity in urine in more than 50% of samples.Only two cytokines measured in urine increased in response to surgically‐induced tissue trauma, and neither responded to the same extent as measurements of suPAR, a previously validated urinary biomarker of inflammation.Urinary measurements of cytokines using the Luminex platform are overall unpromising for studies of macaques, and potentially other primates. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma associated with chronic inflammation (DLBCL‐CI) develops in the setting of long‐standing inflammation. This type of lymphoma may have specific expression profiles of chemokines involved in the pathogenesis of DLBCL‐CI. EBV‐positive pyothorax‐associated lymphoma (PAL) is a prototype of DLBCL‐CI and represents a valuable model for the study of this disease category. Using a panel of PAL cell lines, we found that PAL cells expressed and secreted C–X–C motif chemokine ligands 9 and 10 (CXCL9 and CXCL10), the ligands of CXCR3, in contrast to EBV‐negative DLBCL cell lines, which did not. Culture supernatants from PAL cell lines attracted CXCR3‐expressing CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells from human peripheral blood mononuclear cells. PAL cells injected into mice also attracted CXCR3‐positive cytotoxic lymphocytes that expressed interferon‐γ. The expression of CXCL9 and CXCL10 was detected in PAL tumor biopsy samples from patients, and CXCR3‐positive lymphocytes were abundant in the tissue samples. Collectively, these findings suggest that CXCL9 and CXCL10 are produced by PAL cells and can elicit cytotoxic responses via CXCR3. This chemokine system is also likely to contribute to tissue necrosis, which is a signature histological feature of DLBCL‐CI. Further studies are warranted to determine whether the CXCL9–CXCL10/CXCR3 axis exerts antitumor effects in DLBCL‐CI. [ABSTRACT FROM AUTHOR]

Interleukin-31 (IL-31), a recently discovered cytokine derived from T helper cells, is involved in chronic dermatitis and pruritus. This study demonstrates for the first time that the IL-31 receptor complex for IL-31 is substantially upregulated in human dermal microvascular endothelial cells after stimulation with interferon-γ (IFN-γ). Activation of the IL-31 receptor complex results in the induction of the intracellular ERK1/2 signaling pathway and downregulation of IFN-γ-induced monokine induced by IFN-γ expression. Inhibitor studies revealed that the IFN-γ-induced IL-31RA upregulation is processed via JNK and PI3 kinase activation. In sum, our study points toward an interaction between the TH1-derived cytokine IFN-γ and the TH2-derived cytokine IL-31 on endothelial cells. [ABSTRACT FROM AUTHOR]

Summary: While fundamental in their innate role in combating infection and responding to injury, neutrophils are emerging as key modulators of adaptive immune responses. Such functions are attained via both soluble and nonsoluble effectors that enable at least two major downstream outcomes: first, to mediate and control acute inflammatory responses and second, to regulate adaptive immunity and ultimately promoting the development and maintenance of immune tolerance either by releasing immuno‐modulatory factors, including cytokines, or by directly interacting with cells of the adaptive immune system. Herein, we review these novel properties of neutrophils and redefine the pathophysiological functions of these fascinating multi‐tasking cells, exploring the different mechanisms through which neutrophils are able to either enhance and orchestrate T cell pro‐inflammatory responses or inhibit T cell activity to maintain immune tolerance. [ABSTRACT FROM AUTHOR]

Background: Hepatitis E virus (HEV) infection causes serious adverse pregnancy outcomes during pregnancy. However, the maternal and fetal damage induced by HEV infection is rarely reported. Methods: A BALB/c pregnant mouse model was established to explore the maternal and fetal pathological damage and inflammatory responses caused by HEV infection. Results: Notably, miscarriages and stillbirths were observed in HEV‐infected pregnant mice. HEV infections were identified by qRT‐PCR, immunohistochemical analysis and immunofluorescence assay in the uterus, placenta, umbilical cords and livers and brains of fetuses. Serious inflammatory responses and pathological damage were triggered in the uterus and placenta of HEV‐infected pregnant mice. Vertical transmission of HEV resulted in severe pathological damage and inflammatory responses in the livers and brains of fetuses, as well as emerging apoptosis cells in the brains of fetuses. Most of the cytokines/chemokines in the sera were significantly increased in the HEV‐infected pregnant mice. Remarkably, cytokines/chemokines were significantly different between HEV‐infected pregnant and miscarriage mice; IL9, GM‐CSF and IL1α were the most important three cytokines/chemokines in determining the pregnancy outcomes. Conclusion: HEV infections cause serious maternal/fetal pathological damage, inflammatory responses and apoptosis, which may be responsible for adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Mediators of inflammation, oxidative stress, and chemoattractants drive the hypoxemic mechanisms that accompany pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis commonly have obstructive sleep apnea, which potentiates the hypoxic stimuli for oxidative stress, culminating in systemic inflammation and generalized vascular endothelial damage. Comorbidities like pulmonary hypertension, obesity, gastroesophageal reflux disease, and hypoxic pulmonary vasoconstriction contribute to chronic hypoxemia leading to the release of proinflammatory cytokines that may propagate clinical deterioration and alter the pulmonary fibrotic pathway. Tissue inhibitor of metalloproteinase (TIMP-1), interleukin- (IL-) 1α, cytokine-induced neutrophil chemoattractant (CINC-1, CINC-2α/β), lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG-1), macrophage inflammatory protein- (MIP-) 1α, MIP-3α, and nuclear factor- (NF-) κB appear to mediate disease progression. Adipocytes may induce hypoxia inducible factor (HIF) 1α production; GERD is associated with increased levels of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and tumor necrosis factor alpha (TNF-α); pulmonary artery myocytes often exhibit increased cytosolic free Ca2+. Protein kinase C (PKC) mediated upregulation of TNF-α and IL-1β also occurs in the pulmonary arteries. Increased understanding of the inflammatory mechanisms driving hypoxemia in pulmonary fibrosis and obstructive sleep apnea may potentiate the identification of appropriate therapeutic targets for developing effective therapies. [ABSTRACT FROM AUTHOR]

The beneficial effects of Ginkgo biloba on cardio‐metabolic markers have been reported. However, its effect on inflammation is not assessed in any meta‐analysis. We performed a systematic review of randomized controlled trials evaluating the effects of Ginkgo biloba leaf extract (GBLE) on serum C‐reactive protein (CRP), interleukin‐6 (IL‐6), and tumor necrosis factor‐α (TNF‐α) levels. A systematic search was performed on four databases, including PubMed, Scopus, Web of Science, and Google Scholar, up to October 2021. After screening, 17 trials met our inclusion criteria. Trials were of 1–24 weeks of duration and included 1,104 participants. In the meta‐analysis, the weighted mean differences (WMD) in change for serum CRP were −1.5 mg/L (95% CI: −2.16, −0.85, p < 0.001). Moreover, WMD for serum IL‐6 and TNF‐α were in favor of the GBLE compared to the placebo [(−16.86 pg/mL, 95% CI: −19.38, −14.34, p < 0.001); and (−4.19 pg/mL, 95%CI: −5.14, −3.23, p < 0.001), respectively]. Subgroup analysis showed that GBLE has a beneficial effect on serum CRP at the baseline levels≥3 mg/L and doses<500 mg/day. This meta‐analysis showed that the GBLE could reduce serum inflammatory markers. Therefore, this medicinal herb might be a possible strategy for inflammation control. [ABSTRACT FROM AUTHOR]

To detect the expression of inflammatory factors such as interleukin-1β (IL-1β), interleukin-6 (IL-6), transforming growth factor (TGF-β), and tumor necrosis factor (TNF-α) in the tumor tissue of ventricular septal defect (VSD) in congenital heart disease and to explore the role of inflammatory response in the formation of aneurysmal perimembranous VSD(APVSD). Children with APVSD of congenital heart disease treated by surgery were selected and divided into true aneurysmal perimembranous group (TAP group) and pseudoaneurysmal perimembranous group (PAP group) according to echocardiography and surgical findings. There were 15 children in the TAP group and 31 in the PAP group. The aneurysmal perimembranous tissue of the two groups of children was collected during the operation. IL-1β, IL-6, TGF-β, and TNF-α were positively expressed in the aneurysmal perimembranous tissue of the two groups, and the expression levels of all inflammatory factors in the PAP group were higher than those in the TAP group, and the difference was statistically significant (P < 0.05). The expression levels of IL-1β, IL-6, TGF-β, and TNF-α in the aneurysmal perimembranous tissue of the two groups were negatively correlated with the width of the APVSD breach. IL-1β, IL-6, TGF-β, and TNF-α may be involved in the occurrence and development of APVSD through inflammatory mechanism. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) has emerged as a significant health threat worldwide. Although typically mosquito‐borne, recent evidence suggests that ZIKV is also a sexually transmitted virus. While persistent ZIKV infections in male reproductive tissues have been identified, little is understood regarding the outcomes of primary sexual transmission in females. We investigated how the route of infection affects vaginal ZIKV shedding and dissemination. In two mouse models, vaginal infection resulted in prolonged ZIKV shedding in the vaginal mucosa with delayed systemic infection. Furthermore, heightened vaginal inflammation did not influence ZIKV replication or dissemination, in contrast to previous studies of mosquito‐borne infection. Thus, vaginal infection significantly alters ZIKV infection kinetics and must be considered when developing novel treatments. [ABSTRACT FROM AUTHOR]

Objective: Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high‐mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co‐occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA‐LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA‐LD. Methods: We used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA‐LD, or other related diseases. We verified selected findings by enzyme‐linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA‐LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort. Results: Proteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat‐shock proteins and glycolytic enzymes. Interleukin‐18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA‐LD. We also identified an MAS‐independent SJIA‐LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM‐5), matrix metalloproteinase 7 (MMP‐7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM‐5 and MMP‐7 in the lungs of patients with SJIA‐LD. The ability of ICAM‐5 to distinguish SJIA‐LD from systemic JIA/MAS was independently validated. Conclusion: Serum proteins support a systemic JIA–to‐MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA‐LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM‐5, could aid in early detection and management of SJIA‐LD. [ABSTRACT FROM AUTHOR]

Background and Purpose: Benzoxathiolone derivatives have shown anti-inflammatory and immunomodulatory potential in acne and psoriatic disorders. However, little is known about the molecular basis for these pharmacological effects. In this study, we decided to investigate the anti-inflammatory actions of a benzoxathiolone derivative LYR-71, 6-methyl-2-propylimino-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one, in interferon (IFN)-gamma-activated macrophages.Experimental Approach: RAW 264.7 macrophages or primary macrophages, derived from bone marrow of C3H/HeJ mice, were stimulated with IFN-gamma in the presence of LYR-71. Nitric oxide (NO) or chemokine production was measured by Griess reaction or enzyme-linked immunosorbent assay. RAW 264.7 cells were used to examine the molecular mechanisms of LYR-71 in modulating IFN-gamma-induced inflammatory responses.Key Results: LYR-71 down-regulated IFN-gamma-induced transcription of inducible NO synthase, IFN-gamma-inducible protein-10 and the monokine induced by IFN-gamma genes in macrophages. This effect was mediated by uncoupling tyrosine phosphorylation of the signal transducer and activator of transcription (STAT)-1 in response to IFN-gamma. LYR-71 directly inhibited the in vitro catalytic activity of Janus kinase (JAK)-2. Further, the inhibitory actions of LYR-71 on IFN-gamma-induced STAT-1 phosphorylation and NO production were consistently abolished in the presence of peroxyvanadate, implying another target dependent on protein tyrosine phosphatase.Conclusions and Implications: Taken together, LYR-71 could restrain IFN-gamma-induced inflammatory responses through uncoupling the tyrosine phosphorylation of STAT-1, an activation index of JAK-STAT-1 signalling, in macrophages. These results may provide a molecular mechanism underlying anti-inflammatory actions shown by benzoxathiolone derivatives. [ABSTRACT FROM AUTHOR]

Unravelling the molecular mechanisms that account for functional pleiotropy is a major challenge for researchers in cytokine biology. Cytokine–receptor cross-reactivity and shared signalling pathways are considered primary drivers of cytokine pleiotropy. However, reports epitomized by studies of Jak-STAT cytokine signalling identify interesting biochemical and epigenetic determinants of transcription factor regulation that affect the delivery of signaldependent cytokine responses. Here, a regulatory interplay between STAT transcription factors and their convergence to specific genomic enhancers support the fine-tuning of cytokine responses controlling host immunity, functional identity, and tissue homeostasis and repair. In this review, we provide an overview of the signalling networks that shape the way cells sense and interpret cytokine cues. With an emphasis on the biology of interleukin-6, we highlight the importance of these mechanisms to both physiological processes and pathophysiological outcomes. [ABSTRACT FROM AUTHOR]

Neutrophils are known to play an important role in inflammatory responses by virtue of their ability to perform a series of effector functions that collectively represent a major mechanism of innate immunity against injury infection. In recent years, however, it has become obvious that the contribution of neutrophils to host defence and natural immunity extends well beyond their traditional role as professional phagocytes. Indeed, neutrophils can be induced to express a number of genes whose products lie at the core of inflammatory and immune response. These include not only Fc receptors, complement components, cationic antimicrobial and NADPH oxidase proteins, but also a variety of cytokines (including tumour necrosis factors-α, interleukin (IL)-1Β, IL-1Rα, IL-12 and vascular endothelial growth factor), and chemokines such as IL-8, growth-related gene product, macrophage inflammatory protein (MIP)-1α, MIP-1Β interferon-γ-inducible protein of 10 kDa and monokine induced by interferon-γ. Because these chemokines are primarily chemotactic for neutrophils, monocytes, immature dendritic cells and T-lymphocyte subsets, a potential role for neutrophils in orchestrating the sequential recruitment of distinct leukocyte types to the inflamed tissue is likely to occur. The purpose of this review is to summarize the essential features of the production of chemokines by polymorphonuclear neutrophil leukocytes and the contribution that we have made to characterize some aspects of this newly discovered crucial function of neutrophils. [ABSTRACT FROM AUTHOR]

Macrophages are leukocytes that play a strategic role in immune response and can be associated with various diseases due to their effects on the inflammation process and oxidative events. The current study was evaluated the anti‐inflammatory and antioxidant properties of cinnamaldehyde and eugenol, which are phyto‐compounds with numerous bioactive properties, on lipopolysaccharide (LPS)‐induced macrophage cells. For this purpose, Raw 264.7 cells were incubated with cinnamaldehyde or eugenol (15, 25, and 50 μM) then stimulated with LPS. After 24 hr, tumor necrosis factor‐alpha (TNF‐α), interleukin‐1β (IL‐1β), and IL‐6 levels (as inflammatory mediators), and malondialdehyde (MDA) and nitric oxide (NOx) levels as well as superoxide dismutase (SOD) and catalase (CAT) activities (as oxidative status markers) were determined in cell cultures. Cinnamaldehyde and eugenol pre‐treatments decreased TNF‐α, IL‐1β, and IL‐6 levels as compared to LPS group at all concentrations. Furthermore, these pre‐treatments increased SOD activity while decreased MDA and NOx levels as well as CAT activity at different concentrations. Our results demonstrated that these phyto‐compounds have potential for the treatment of various diseases as protective agents against chronic inflammation and oxidative stress. Practical applications: Chronic inflammation and oxidative stress are complications that play a detrimental role in the pathophysiology of many diseases. Alternative treatment methods have been investigated to prevent them. Cinnamaldehyde and eugenol are phyto‐compounds with high bioactivity that can be obtained from foods and spices. In this study, the protective effects of cinnamaldehyde and eugenol on lipopolysaccharide‐induced oxidative stress and inflammation in macrophage cells were investigated. According to the obtained results, cinnamaldehyde and eugenol pre‐treatments decreased inflammation and also reduced oxidative stress. Cinnamaldehyde and eugenol may be a better natural alternative protective agent for the chronic inflammation‐ and oxidative stress‐related diseases. [ABSTRACT FROM AUTHOR]

Background: Previous investigations suggest the use of extract from the roots of Pelargonium sidoides (EPs 7630) for the therapy of uncomplicated rhinosinusitis. The aim of this prospective study was to compare the effects of herbal drug EPs 7630 and antibiotic roxithromycin on chemokine production in nasal mucosa and clinical parameters in patients with uncomplicated acute bacterial rhinosinusitis (ABRS). Methods: Seventy‐eight ABRS patients were divided into 26 patients receiving EPs 7630 tablets, 3 × 20 mg/day per os (group 1), 26 patients receiving roxithromycin tablets, 2 × 150 mg/day per os (group 2), both for 10 days, and 26 patients who received no therapy (Control group). We measured chemokine levels in nasal secretions by flow cytometry and assessed clinical parameters on day 0 and day 10 of investigation. Results: EPs 7630 increased concentrations of MCP‐1 (P =.001) and IP‐10 (P =.049) and decreased levels of MIP‐1α (P <.001), ENA‐78 (P <.001), and IL‐8 (P <.001). Roxithromycin increased levels of IP‐10 (P =.049) and decreased levels of MCP‐1 (P <.001), MIP‐1α (P <.016), ENA‐78 (P <.001), and IL‐8 (P <.001). Comparison of the non‐treated patients' group with groups 1 and 2 revealed significant improvement of all clinical parameters in treated patients (P <.001), but therapy with roxithromycin resulted in better improvement in nasal symptoms and endoscopic findings than therapy with EPs 7630. Conclusion: Our results suggest the presence of similar modulatory effects of both therapies on production of chemokines that regulate the function of neutrophils and monocytes in nasal mucosa. Roxithromycin shows better clinical efficacy than EPs 7630 in patients with uncomplicated ABRS. Level of Evidence: 1b. [ABSTRACT FROM AUTHOR]

Inflammation is considered to play a pivotal role in the pathogenesis of cancer, and observational studies have reported a relationship between circulating inflammation markers and the risk of prostate cancer. Using summary data of >140 000 individuals, two‐sample Mendelian randomization (MR) analyses were performed to evaluate whether circulating levels of 27 cytokines and growth factors have a causal effect on the risk of developing prostate cancer. Genetically predicted elevated levels of monocyte chemotactic protein‐1 (MCP‐1) were associated with an increased risk of prostate cancer (odds ratio (OR) per 1 SD increase = 1.06, 95% confidence interval (CI): 1.04‐1.09) at Bonferroni‐adjusted level of significance (P < 1.85 × 10−3). Results were stable across sensitivity analyses, and there was no evidence of directional pleiotropy. Under MR assumptions, our findings suggested a risk‐increasing effect of circulating MCP‐1 levels on prostate cancer. Whether targeting MCP‐1 or its downstream effectors are useful in reducing prostate cancer incidence needs further investigation. What's new? Observational studies have reported a relationship between circulating inflammation markers and the risk of prostate cancer. However, these studies cannot exclude potential confounders due to the nature of their traditional design. Here, the authors first performed two‐sample Mendelian randomisation analysis to investigate the potential causal effects of 27 cytokines and growth factors on prostate cancer risk. The results suggested that genetically‐predicted, life‐long elevated levels of circulating monocyte chemotactic protein‐1 (MCP‐1) were associated with a higher risk of prostate cancer. The finding provides supportive evidence of a causal association and hints at MCP‐1 as a potential therapeutic target for prostate cancer. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor alpha (TNF‐α) is an inflammatory cytokine produced during acute inflammation. Few studies have evaluated the association between serum TNF‐α and its receptors and their clinical outcomes in hemodialysis patients. However, a study assessing patients using a low‐flux dialyzer reuse has not been conducted yet. The serum TNF‐α concentrations of 319 prevalent hemodialysis patients (mean age, 45 ± 15 years; median duration of hemodialysis, 48 [interquartile range, 26‐79] months; 185 males and 134 females) was examined to predict their 3‐year mortality. The patients were divided into tertiles according to their serum TNF‐α concentrations: T1 (n = 106; serum TNF‐α concentration, <41.22 pg/mL), T2 (n = 106; serum TNF‐α level, from 41.22 to 67.28 pg/mL), and T3 (n = 107; serum TNF‐α concentration, ≥ 67.29 pg/mL). During the 36‐month follow‐up period, a total of 50 (15.7%) patients died from all causes. The Kaplan‐Meier analysis revealed that the all‐cause mortality in T3 was significantly higher compared to that in T1 and T2 (log‐rank test, P <.001). The serum TNF‐α level was a significant predictor for all‐cause mortality (area under the curve = 0.887, P <.001, cutoff value, 89.812 pg/mL, sensitivity = 76%, specificity = 96.3%). The serum TNF‐α level was a better predictor of mortality than the duration of hemodialysis and serum albumin, serum high‐sensitivity C‐reactive protein, and serum beta‐2 microglobulin concentrations. The serum TNF‐α concentration was a good predictor of the 3‐year mortality in low‐flux hemodialysis patients. [ABSTRACT FROM AUTHOR]

Background: Vagal nerve stimulation has been reported to treat inflammation with promising results. The aims of our study were to optimize sacral nerve stimulation (SNS) methodologies for colonic inflammation in a rodent model of colitis and to investigate autonomic and cytokine mechanisms. Methods: Three major efforts were made in optimizing SNS: (a) to determine the best stimulation duration: SNS‐0.5h daily, SNS‐1h daily, and SNS‐3h daily with the parameters set at 5 Hz, 10 seconds on, 90 seconds off; (b) to determine the best stimulation position: bilateral, bipolar, and unipolar stimulation; (c) to determine the best stimulation parameters: our 5 Hz intermittent stimulation vs 14 Hz‐210 μs continuous stimulation. Inflammatory responses were assessed by the disease activity index (DAI), histological analyses, and the myeloperoxidase (MPO) activity. Levels of inflammatory cytokines, norepinephrine (NE), and pancreatic polypeptide (PP) in both plasma and colon tissues were assessed. Key Results: Both SNS‐1h and SNS‐3h significantly ameliorated intestinal inflammation; SNS‐1h was superior to SNS‐3h. Bipolar but not bilateral or unipolar stimulation improved the inflammation in colitis. SNS with 5 Hz intermittent stimulation but not the 14 Hz continuous SNS was better for treating colitis in rats. SNS with the optimized stimulation parameters increased vagal activity and decreased sympathetic activity. Conclusion & Inferences: Bipolar stimulation for 1 hour daily using intermittent 5 Hz parameters is most effective in improving colonic inflammation in TNBS‐treated rats by inhibiting pro‐inflammatory cytokines and increasing anti‐inflammatory cytokines via the modulation of the autonomic function. [ABSTRACT FROM AUTHOR]

The body's autoimmune process is involved in the development of Graves' disease (GD), which is manifested by an overactive thyroid gland. In some patients, autoreactive inflammatory reactions contribute to the development of symptoms such as thyroid ophthalmopathy, and the subsequent signs and symptoms are derived from the expansion of orbital adipose tissue and edema of extraocular muscles within the orbit. The autoimmune process, production of antibodies against self-antigens such as TSH receptor (TSHR) and IGF-1 receptor (IGF-1R), inflammatory infiltration, and accumulation of glycosaminoglycans (GAG) lead to edematous-infiltrative changes in periocular tissues. As a consequence, edema exophthalmos develops. Orbital fibroblasts seem to play a crucial role in orbital inflammation, tissue expansion, remodeling, and fibrosis because of their proliferative activity as well as their capacity to differentiate into adipocytes and myofibroblasts and production of GAG. In this paper, based on the available medical literature, the immunological mechanism of GO pathogenesis has been summarized. Particular attention was paid to the role of orbital fibroblasts and putative autoantigens. A deeper understanding of the pathomechanism of the disease and the involvement of immunological processes may give rise to the introduction of new, effective, and safe methods of treatment or monitoring of the disease activity. [ABSTRACT FROM AUTHOR]

Substance use disorders are global health problems with few effective treatment options. Unfortunately, most potential pharmacological treatments are hindered by abuse potential of their own, limited efficacy, or adverse side effects. As a consequence, there is a pressing need for the development of addiction treatments with limited abuse potential and fewer off target effects. Given the difficulties in developing new pharmacotherapies for substance use disorders, there has been growing interest in medications that act on non‐traditional targets. Recent evidence suggests a role for dysregulated immune signaling in the pathophysiology of multiple psychiatric diseases. While there is evidence that immune responses in the periphery and the central nervous system are altered by exposure to drugs of abuse, the contributions of neuroimmune interactions to addictive behaviors are just beginning to be appreciated. In this review, we discuss the data on immunological changes seen in clinical populations with substance use disorders, as well as in translational animal models of addiction. Importantly, we highlight those mechanistic findings showing causal roles for central or peripheral immune mediators in substance use disorder and appropriate animal models. Based on the literature reviewed here, it is clear that brain‐immune system interactions in substance use disorders are much more complex and important than previously understood. While much work remains to be done, there are tremendous potential therapeutic implications for immunomodulatory treatments in substance use disorders. [ABSTRACT FROM AUTHOR]

Aim: To assess the inflammatory potential of biofilm matrix constituents of Enterococcus faecalis and Pseudomonas aeruginosa monospecies biofilms on macrophages. Methodology: In vitro biofilms of E. faecalis and P. aeruginosa were grown (7 days) in aerobic and anaerobic conditions. The biofilm matrix components: exopolysaccharides (EPS) and extracellular DNA (eDNA) were extracted and quantified. The inflammatory potential of EPS and eDNA was assessed on macrophage cell lines (RAW 267.4) using nitric oxide (NO), and enzyme‐linked immunosorbent assay for tumour necrosis factor (TNF‐α) and interleukin‐6 (IL‐6) expressions. LPS from P. aeruginosa and planktonic bacteria were positive controls. One‐way analysis of variance and the Tukey post hoc test were used for statistical analysis. Results: Extracted EPS from both biofilm strains was associated with higher levels than eDNA in both growth conditions (P < 0.05). The biofilm components had less inflammatory potential compared to planktonic bacteria and LPS. EPS produced higher levels of inflammatory response compared to eDNA for both strains (P < 0.05). IL‐6 and TNF‐α, and NO expression showed no difference for E. faecalis EPS (P ≥ 0.05). In contrast, P. aeruginosa EPS and eDNA had significant levels of IL‐6 compared to TNF‐α and NO (P < 0.05). Conclusions: Monospecies biofilm matrix EPS and eDNA from the bacterial strains tested had the ability to induce a low‐grade inflammatory response when compared to planktonic bacteria and LPS. This study highlights the potential of biofilm matrix/components, devoid of bacteria to induce low‐grade chronic inflammation. [ABSTRACT FROM AUTHOR]

Background: Beyond their role in hemostasis and thrombosis, platelets are also important mediators of inflammation by the release of hundreds of factors stored in their α-granules. Mutations in Nbeal2 cause gray platelet syndrome (GPS), characterized by the lack of platelet α-granules. This study aims to evaluate the immunological (proinflammatory) effects of platelet α-granules.Study Design and Methods: We performed an experiment using Nbeal2-/- mice, the mouse model of GPS. Systemic inflammation was induced by intravenous injection of lipopolysaccharide (LPS). Inflammatory response was assessed by quantification of inflammatory soluble factors and platelet biological response modifiers.Results: The lack of Nbeal2 (in Nbeal2 -/- mice, compared with controls) significantly reduced the recruitment of circulating neutrophils and monocytes. Moreover, after LPS injection, there was a significant increase in neutrophil and monocyte counts in control animals, compared with Nbeal2 -/- mice. The control of inflammation, evaluated by the production of anti-inflammatory cytokines, appeared to be greater in Nbeal2-/- mice compared with controls. Conversely, the production of certain inflammatory-soluble mediators known to characterize normal platelet secretion, such as soluble CD40 ligand (sCD40L), was decreased under experimental inflammation in Nbeal2 -/- mice.Conclusions: These results show that α-granules play a direct role in platelet-mediated inflammation balance, confirming the need to further investigate platelet-associated inflammatory pathophysiology and inflammatory adverse events related to blood transfusion. [ABSTRACT FROM AUTHOR]

Summary: Chronic hepatitis D is caused by coinfection of hepatitis B and hepatitis D virus. While HDV is the dominant virus over HBV in the majority of cases, mechanisms and consequences of viral dominance are largely unknown. We aimed to investigate associations between viral dominance patterns and patients' characteristics and inflammatory features; 109 HDV‐infected patients treated with PEG‐IFNa‐2α within the international multicentre, prospective HIDIT‐2 trial were studied. Patients were classified as D‐ or B‐dominant if the viral load of one virus exceeded that of the other virus by more than 1log10. Otherwise, no viral dominance (ND) was described. We used Luminex‐based multiplex technology to study 50 soluble immune mediators (SIM) in pretreatment samples of 105 HDV RNA‐positive patients. Dominance of HDV was evident in the majority (75%) of cases. While only 7% displayed B‐dominance, 17% showed nondominance. D‐dominance was associated with downregulation of 4 interleukins (IL‐2ra, IL‐13, IL‐16 and IL‐18) and 5 chemokines/cytokines (CTACK (CCL27), MCP‐1 (CCL2), M‐CSF, TRAIL and ICAM‐1) while no analyte was increased. In addition, D‐dominance could be linked to a delayed HDV RNA response to pegylated interferon as patients with B‐dominance or nondominance showed higher early HDV RNA responses (61% at week 12) than D‐dominant patients (11%; P < .001). In conclusion, this study revealed unexpected effects of viral dominance on clinical and immunological features in chronic hepatitis delta patients. Individualizing PEG‐IFNa‐2α treatment duration should consider viral dominance. Overall, our findings suggest an activated but exhausted IFN system in D‐dominant patients. [ABSTRACT FROM AUTHOR]

Abstract: Acute liver failure (ALF) is associated with high mortality, and a poor understanding of the underlying pathophysiology has resulted in a lack of effective treatments so far. Here, using an amatoxin‐induced rhesus monkey model of ALF, we panoramically revealed the cellular and molecular events that lead to the development of ALF. The challenged monkeys with toxins underwent a typical course of ALF including severe hepatic injury, systemic inflammation and eventual death. Adaptive immune was not noticeably disturbed throughout the progress of ALF. A systematic examination of serum factors and cytokines revealed that IL‐6 increase was the most rapid and drastic. Interestingly, we found that IL‐6 was mainly produced by circulating monocytes. Furthermore, ablation of monocyte‐derived IL‐6 in mice decreased liver injury and systemic inflammation following chemical injection. Our findings reveal a critical role of circulating monocytes in initiating and accelerating ALF, indicating a potential therapeutic target in clinical treatment for ALF. [ABSTRACT FROM AUTHOR]

Abstract: Urinary CXCL10 and metabolites are biomarkers independently associated with TCMR. We sought to test whether these biomarkers fluctuate in association with histological severity of TCMR over short time frames. Forty‐nine pairs of renal biopsies obtained 1‐3 months apart from 40 pediatric renal transplant recipients were each scored for TCMR acuity score (i + t; Banff criteria). Urinary CXCL10:Cr and TCMR MDS were obtained at each biopsy and were tested for association with changes between biopsies in acuity, estimated GFR (ΔeGFR), and 12‐month ΔeGFR. Sequential biopsies were obtained 1.8 ± 0.8 months apart. Biopsy 1 was usually obtained under protocol (75%), and 62% percent had evidence of TCMR. Using each biopsy pair for comparison, ΔeGFR did not predict change in acuity. By contrast, change in acuity was significantly correlated with change in urinary CXCL10:Cr (ρ 0.45, P = .003) and MDS (ρ 0.29, P = .04) between biopsies. The 12‐month ΔeGFR was not predicted by TCMR acuity or CXCL10:Cr at Biopsy 2; however, an inverse correlation was seen with urinary MDS (ρ −0.35; P = .02). Changes in eGFR correlate poorly with evolving TCMR acuity on histology. Urinary biomarkers may be superior for non‐invasive monitoring of rejection, including histological response to therapy, and may be prognostic for medium‐term function. [ABSTRACT FROM AUTHOR]

ABSTRACT Over 25 years have passed since peroxisome proliferators-activated receptors ( PPARs), were first described. Like other members of the nuclear receptors superfamily, PPARs have been defined as critical sensors and master regulators of cellular metabolism. Recognized as ligand-activated transcription factors, they are involved in lipid, glucose and amino acid metabolism, taking part in different cellular processes, including cellular differentiation and apoptosis, inflammatory modulation and attenuation of acute and chronic neurological damage in vivo and in vitro. Interestingly, PPAR activation can simultaneously reprogram the immune response, stimulate metabolic and mitochondrial functions, promote axonal growth, induce progenitor cells to differentiate into myelinating oligodendrocytes, and improve brain clearance of toxic molecules such as β-amyloid peptide. Although the molecular mechanisms and cross-talk with different molecular pathways are still the focus of intense research, PPARs are considered potential therapeutic targets for several neuropathological conditions, including degenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. This review considers recent advances regarding PPARs, as well as new PPAR agonists. We focus on the mechanisms behind the neuroprotective effects exerted by PPARs and summarise the roles of PPARs in different pathologies of the central nervous system, especially those associated with degenerative and inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Medial degeneration associated with thoracic aortic aneurysm and acute aortic dissection was originally described by Erdheim as a noninflammatory lesion related to the loss of smooth muscle cells and elastic fibre fragmentation in the media. Recent evidences propose the strong role of a chronic immune/inflammatory process in aneurysm evocation and progression. The coexistence of inflammatory cells with markers of apoptotic vascular cell death in the media of ascending aorta with aneurysms and type A dissections raises the possibility that activated T cells and macrophages may contribute to the elimination of smooth muscle cells and degradation of the matrix. On the other hand, several inflammatory pathways (including TGF-β, TLR-4 interferon-γ, chemokines, and interferon-γ) seem to be involved in the medial degeneration related to aged and dilated aorta. This is an overview on thoracic aortic aneurysm as an emerging inflammatory disease. [ABSTRACT FROM AUTHOR]

Novel evidence-based prosthetic designs and biomaterials facilitate the performance of highly successful joint replacement (JR) procedures. To achieve this goal, constructs must be durable, biomechanically sound, and avoid adverse local tissue reactions. Different biomaterials such as metals and their alloys, polymers, ceramics, and composites are currently used for JR implants. This review focuses on (1) the biological response to the different biomaterials used for TJR and (2) the chronic inflammatory and foreign-body response induced by byproducts of these biomaterials. A homeostatic state of bone and surrounding soft tissue with current biomaterials for JR can be achieved with mechanically stable, infection free and intact (as opposed to the release of particulate or ionic byproducts) implants. Adverse local tissue reactions (an acute/chronic inflammatory reaction, periprosthetic osteolysis, loosening and subsequent mechanical failure) may evolve when the latter conditions are not met. This article (Part 2 of 2) summarizes the biological response to the non-metallic materials commonly used for joint replacement including polyethylene, ceramics, and polymethylmethacrylate (PMMA), as well as the foreign body reaction to byproducts of these materials. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1685-1691, 2017. [ABSTRACT FROM AUTHOR]

Acute spinal cord injury ( SCI) has become epidemic in modern society. Despite advances made in the understanding of the pathogenesis and improvements in early recognition and treatment, it remains a devastating event, often producing severe and permanent disability. SCI has two phases: acute and secondary. Although the acute phase is marked by severe local and systemic events such as tissue contusion, ischaemia, haemorrhage and vascular damage, the outcome of SCI are mainly influenced by the secondary phase. SCI causes inflammatory responses through the activation of innate immune responses that contribute to secondary injury, in which polarization-based macrophage activation is a hallmarker. Macrophages accumulated within the epicentre and the haematoma of the injured spinal cord play a significant role in this inflammation. Depending on their phenotype and activation status, macrophages may initiate secondary injury mechanisms and/or promote CNS regeneration and repair. When it comes to therapies for SCI, very few can be performed in the acute phase. However, as macrophage activation and polarization switch are exquisitely sensitive to changes in microenvironment, some trials have been conducted to modulate macrophage polarization towards benefiting the recovery of SCI. Given this, it is important to understand how macrophages and SCI interrelate and interact on a molecular pathophysiological level. This review provides a comprehensive overview of the immuno-pathophysiological features of acute SCI mainly from the following perspectives: (i) the overview of the pathophysiology of acute SCI, (ii) the roles of macrophage, especially its polarization switch in acute SCI, and (iii) newly developed neuroprotective therapies modulating macrophage polarization in acute SCI. [ABSTRACT FROM AUTHOR]

Systemic immune activation is a striking consequence of HIV-1 infection. Even in virologically suppressed patients, some hyperactivity of the immune system and even of the endothelium and of the coagulation pathway may persist. Apart from immune deficiency, this chronic activation may contribute to various morbidities including atherothrombosis, neurocognitive disorders, liver steatosis and osteoporosis, which are currently main challenges. It is therefore of major importance to better understand the causes and the phenotypes of immune activation in the course of HIV-1 infection. In this review we will discuss the various causes of immune activation in HIV-1 infected organisms: the presence of the virus together with other microbes, eventually coming from the gut, CD4+ T cell lymphopenia, senescence and dysregulation of the immune system, and/or genetic factors. We will also describe the activation of the immune system: CD4+ and CD8+ T cells, B cells, NKT and NK cells, dendritic cells, monocytes and macrophages, and neutrophils of the inflammation cascade, as well as of the endothelium and the coagulation system. Finally, we will see that antiretroviral therapy reduces the hyperactivity of the immune and coagulation systems and the endothelial dysfunction, but often does not abolish it. A better knowledge of this phenomenon might help us to identify biomarkers predictive of non AIDS-linked comorbidities, and to define new strategies aiming at preventing their emergence. [ABSTRACT FROM AUTHOR]

The purpose of this study was three fold: (1) to reveal the implications of Wnt5A for cytokine and chemokine production by human ovarian cancer cell line SKOV-3 cells, (2) to determine the influence of Wnt5A on chemotactic SKOV-3 cell migration, and (3) to assess the effect of inflammatory mediators on Wnt5A expression levels and to describe its underlying molecular mechanisms. A cytokine array was performed using a conditioned medium harvested from SKOV-3 cells transfected with specific siRNAs against Wnt5A or with scrambled siRNA and a transfection reagent alone as negative controls for 48 h. Chemotactic cell migration was performed using transwells. Inflammation-induced Wnt5A expression was determined by treating cells with recombinant human (rh) IL-1β, IFNβ, or TNFα alone or in combination with STAT3 and NF-κB inhibitors for different time durations. The cytokine array showed the suppression of GCSF, GM-CSF, IL-1α, IL-2, IL-13, and MCP-3 production, whereas cell RANTES and IL-7 showed increased levels in Wnt5A knock-down cells compared with those in controls. Chemotactic migration decreased significantly when the conditioned medium from Wnt5A knock-down cells was applied to the upper chamber of the transwell. Compared with the control, there were 30-fold and five-fold increases in Wnt5A mRNA levels in cells treated, with rhIL-1β and rhIFNβ, respectively after 8 h ( P < 0.001). Compared with the control, TNF-α had a 1.8-fold increased levels of Wnt5A mRNA after 4 h ( P < 0.01). Both NF-κB and STAT3 inhibitors decreased inflammation-induced Wnt5A expression. This study revealed a previously unrecognized immunomodulatory role of endogenous Wnt5A in ovarian cancer cells, which could further influence chemotactic cell migration. [ABSTRACT FROM AUTHOR]

CD4+ T cells maintain cancer surveillance and immune tolerance. Chronic inflammation has been proposed as a driver of clonal evolution in myeloproliferative neoplasms ( MPN), suggesting that T cells play an important role in their pathogenesis. Treatment with JAK inhibitors ( JAKi) results in improvements in MPN-associated constitutional symptoms as well as reductions in splenomegaly. However, effects of JAKi on T cells in MPN are not well established and the baseline immune signature remains unclear. We investigated the frequency and function of CD4+ T cell subsets in 50 MPN patients at baseline as well as during treatment with either ruxolitinib or fedratinib in a subset. We show that CD4+ CD127low CD25high FOXP3+ T regulatory cells are reduced in MPN patients compared to healthy controls and that this decrease is even more pronounced following JAKi therapy. Moreover, we show that after 6 months of treatment the number of T helper (Th)-17 cells increased. We also describe a functional 'silencing' of T helper cells both in vivo and in vitro and a blockade of pro-inflammatory cytokines from these cells. This profound effect of JAKi on T cell function may underlay augmented rates of atypical infections that have been reported with use of these drugs. [ABSTRACT FROM AUTHOR]

Compared to normal tissues, many cancer cells overexpress autotaxin (ATX). This secreted enzyme produces extracellular lysophosphatidate, which signals through 6 GPCRs to drive cancer progression. Our previous work showed that ATX inhibition decreases 4T1 breast tumor growth in BALB/c mice by 60% for about 11 d. However, 4T1 cells do not produce significant ATX. Instead, the ATX is produced by adjacent mammary adipose tissue. We investigated the molecular basis of this interaction in human and mouse breast tumors. Inflammatory mediators secreted by breast cancer cells increased ATX production in adipose tissue. The increased lysophosphatidate signaling further increased inflammatory mediator production in adipose tissue and tumors. Blocking ATX activity in mice bearing 4T1 tumors with 10 mg/kg/d ONO-8430506 (a competitive ATX inhibitor, IC90 = 100 nM; Ono Pharma Co., Ltd., Osaka, Japan) broke this vicious inflammatory cycle by decreasing 20 inflammatory mediators by 1.5-8-fold in cancer-inflamed adipose tissue. There was no significant decrease in inflammatory mediator levels in fat pads that did not bear tumors. ONO-8430506 also decreased plasma TNF-α and G-CSF cytokine levels by >70% and leukocyte infiltration in breast tumors and adjacent adipose tissue by >50%. Hence, blocking tumor-driven inflammation by ATX inhibition is effective in decreasing tumor growth in breast cancers where the cancer cells express negligible ATX. [ABSTRACT FROM AUTHOR]