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[Display omitted] • PLD patients consistently showed higher IL-6 concentrations than controls. • PLD patients had higher IL-1β and IL-1Ra concentrations in response to S. aureus and C. albicans. • Controls had higher IL-8 and TNF concentrations in response to Gram-negative bacteria, • No differences were found in IL-17, IL-22, and IFN-γ concentrations after 7 days. • Differences were independent of demographic and clinical factors. The role of the innate immune system in polycystic liver disease (PLD) has been underexplored despite its potential importance in disease progression. This study explores the innate immune response in PLD patients by analyzing cytokine production of peripheral blood mononuclear cells (PBMCs) in response to various pathogens compared to healthy controls. Samples were collected from patients with ADPLD or ADPKD and PLD. PBMCs were isolated and stimulated with LPS (1 ng), LPS (10 ng), E. coli , K. pneumoniae , S. aureus , and C. albicans. ELISA was used to measure TNF, IL-1β, IL-1Ra, IL-6, and IL-8 concentrations after 24 hours, and IL-17, IL-22, and IFNγ concentrations after 7 days. Control samples were matched for age and gender. 104 patients and 12 controls were included. PLD patients showed consistent increased IL-6 concentrations compared to controls. Other cytokine levels varied per stimulus. Controls showed higher IL-8 and TNF concentrations in response to Gram-negative bacteria, while PLD patients showed higher IL-1β and IL-1Ra levels in response to S. aureus and C. albicans. No clear differences were found in IL-17, IL-22, and IFN-γ concentrations after 7 days. These observed differences were independent of demographic and clinical parameters. Compared to healthy controls, the PLD patients innate immune system shows an altered response when stimulated by various pathogens. These findings underscore the importance of further investigation into the underlying mechanisms as this might help our understanding disease progression and be a potential target for new therapies. [ABSTRACT FROM AUTHOR]

• The fungal load in tissues increases depending on host immunity. • The elevated levels of the antibodies production (IgA and IgG) and immunological markers (IL-17, and TLR2) in serum and the gut. Candida species are a normal human flora in humans' digestive and reproductive systems, oral cavity, skin, and mucosal surfaces. This study aimed to detect the immunological role of Candida infection by using some immunological markers. The results of levels in serum showed high concentrations of IgA (56.20 ± 12 pg/ml,29.55 ± 4.5 pg/ml respectively) and IgG (12.05 ± 3.218 pg/ml, 3.836 ± 1.23 pg/ml respectively) in mice infected with C. albicans and mice treated with Cefoperazone and infected with Candida with significant differences (P value < 0.05). The results showed high serum levels of IL-17(191.5 ± 42.81 pg/ml) and TLR2(7.651 ± 1.5 pg/ml) in group mice infected with C. albicans compared with negative control and group mice treated with Cefoperazone. Also, high levels of IL-17 (91.33 ± 4.816 pg/ml) and TLR2 (2.630 ± 0.5 pg/ml) in group mice treated with Cefoperazone and infected with Candida compared with negative control and group mice treated with Cefoperazone (P value < 0.05). The results of antibodies and immunological markers in the intestine showed high levels of IgA and IgG in mice infected with C.albicans (55.7 ± 4.9 pg/ml, 18.19 ± 0.63 pg/ml respectively).Also,IgA and IgG in mice treated with Cefoperazone and infected with Candida were high level (43.04 ± 2.1 pg/ml, 2.927 ± 0.2 pg/ml respectively) in mice infected with C. albicans with significant differences (P value < 0.05). The results levels of IL-17 and TLR2 were increased in mice infected with C. albicans (191.5 ± 42.81 pg/ml, 7.651 ± 1.5 pg/ml respectively) and mice treated with Cefoperazone and infected with Candida (91.33 ± 4.816 pg/ml,2.630 ± 0.5 pg/ml respectively) with significant differences (P < 0.05). In conclusion, this study demonstrated that cefoperazone treatment and infection by Candida albicans changed the microbiome components in the gut and finally can change host immune responses. It was observed that elevated levels of the antibodies production (IgA and IgG) and immunological markers (IL-17, and TLR2) in serum and the gut. [ABSTRACT FROM AUTHOR]

• IL-17 is implicated in many organ-specific and systemic autoinflammatory diseases. • IL-17 exhibits both profibrotic and antifibrotic function in an organ and disease-specific manner. • Defining IL-17 signaling may identify novel drug targets in treating organ fibrosis. Fibrosis affects all vital organs accounting for a staggering 45% of deaths worldwide and no effective therapies are currently available. Unresolved inflammation triggers downstream signaling events that lead to organ fibrosis. In recent years, proinflammatory cytokine Interleukin-17 (IL-17) has been implicated in several chronic inflammatory diseases that often culminate in organ damage followed by impaired wound healing and fibrosis. In this review, we outline the contribution of the IL-17 in mediating fibrotic diseases in various organs. A comprehensive understanding of the inflammatory events, and particularly the details of IL-17 signaling in vivo, could be beneficial in designing new therapeutic or preventive approaches to treat fibrosis. Additionally, understanding organ-specific differences in IL-17 activity could lead to targeted therapies and help spare other organs from unwanted side effects. [ABSTRACT FROM AUTHOR]

• Gastric cancer is a leading cause of cancer related deaths. • A common feature of gastric cancers is an inflammatory microenvironment. • Cytokines are produced in gastric tumours by a range of cell populations. • IL-17 and IL-18 associated cytokines may represent a new therapeutic opportunity. Chronic inflammation is recognized as a key tumor-promoting factor in a number of epithelial cancers, including gastric cancer (GC). The production of pro-inflammatory cytokines in the tumor microenvironment by both the innate and the adaptive immune response can activate signaling pathways that are associated with increased cell survival and proliferation of cancer cells. Among the cytokines that have most commonly been linked to inflammation-associated cancers, are the Th17 cell-associated cytokines IL-17A, IL-23, IL-22, and the IL-1 family members IL-1β and IL-18. However, whether their contribution to inflammation-associated cancers is universal, or specific to individual types of cancers, remains to be elucidated. This review will explore our current understanding of the known roles of these cytokines in gastritis and discuss how their therapeutic inhibition may be useful for GC. [ABSTRACT FROM AUTHOR]

• Case-control study included 479 patients and 483 controls. • SNPs in IL17/IL23 were evaluated for risk and prognosis of gastric cancer. • Two SNPs (rs1884444 and rs6682925) in IL-23R were related OS of patients. IL-17/IL-23 pathway has been hypothesized to play a role in occurrence and progression of gastric cancer. To investigate the susceptibility and prognostic value of polymorphisms in genes in the IL-17/IL-23 pathway to gastric cancer, we performed a case-control study combined a retrospective study in a Chinese population. The Sequenom's MassARRAY® genotyping platform was used to genotype the polymorphisms, and infection of Helicobacter pylori (H. pylori) was determined by using a commercial H. pylori immunogold testing kit. The results showed that IL-17A rs3748067 T allele carriers have a higher gastric cancer risk than non-carriers in the subgroup of individuals with age >64 years old (CT/TT vs. CC: adjusted OR = 1.55, 95% CI = 1.04–2.29). The result of prognosis shown that IL-23R rs1884444 GG and rs6682925 CC genotype were associated with unfavorable survival (rs1884444 GG vs. GT/TT: adjusted HR = 1.40, 95%CI:1.02–1.93; rs6682925 CC vs. CT/TT: HR = 1.43, 95%CI:1.06–1.92), respectively. The stratified analysis revealed that the significant association of rs1884444 was maintained in the subgroup of older than 64 years old, and that rs6682925 was associated with unfavorable survival in the subgroup of female and patients received chemotherapy. In short, we concluded two polymorphisms (rs1884444 and rs6682925) in IL-23R were associated with prognosis of gastric cancer patients. [ABSTRACT FROM AUTHOR]

Highlights • Altered expression of transcription factor of Th17 cells could influence schizophrenia. • Inducer (IL-6) and effector (IL-22) cytokines of Th17 cells could mediate inflammation in schizophrenia. • The components of Th17 pathway can modulate schizophrenia psychopathology. Abstract The immuno-inflammatory origin of schizophrenia in a subset of patients is viewed as a key element of an overarching etiological construct. Despite substantial research, the immune components exerting major effect are yet to be fully clarified. Disrupted T cell networks have consistently been linked to the pathogenesis of schizophrenia. Amongst the Th cell subsets, the Th17 cells have emerged as a paradigmatic lineage with significant functional implications in a vast number of immune mediated diseases including brain disorders such as schizophrenia. The present study was aimed at examining the functional role of the Th17 pathway in schizophrenia. To address this, genotyping of IL17A (rs2275913; G197A) Single Nucleotide Polymorphism was carried out by the PCR-RFLP method in 221 schizophrenia patients and 223 healthy control subjects. Gene expression of two transcription factors STAT3 and RORC was quantified in a subset of drug naïve schizophrenia patients (n = 56) and healthy controls (n = 52) by TaqMan assay. The plasma levels of fifteen cytokines belonging to Th17 pathway were estimated in a subset of drug naïve schizophrenia patients (n = 61) and healthy controls (n = 50) by using Bio-Plex Pro Human Th17 cytokine assays. The AA genotype was associated with higher total score of bizarre behaviour and apathy in female schizophrenia patients. A high gene expression level of RORC was observed in drug naïve schizophrenia patients. In addition, significantly elevated plasma levels of IL-6 and IL-22, and reduced levels of IL-1β and IL-17F were noted in schizophrenia patients. Taken together, these findings indicate a dysregulated Th17 pathway in schizophrenia patients. [ABSTRACT FROM AUTHOR]

Epilepsy is a chronic disorder in which immune dysregulation is shown to be involved. Imbalances in the cytokine levels both in serum and brain tissue have been demonstrated in epileptic patients. In the present study, we assessed mRNA expression of TNF-α, TGF-β, IFN-γ, CXCL8, IL-1β, IL-2, 1L-4, IL-6, IL-17 and CXCL8 in blood samples of 40 epileptic patients compared with age- and sex-matched healthy controls by means of quantitative real time PCR. The relative levels of CXCL8 transcripts were significantly higher in total epileptic patients compared with healthy subjects (P = .023). Relative mRNA expression of IFN-γ was significantly higher in female patients compared with female healthy subject (P = .048). In addition, significant correlations have been found between the mRNA levels of mentioned cytokines. Such imbalance between expression of pro-inflammatory and anti-inflammatory cytokines might be implicated in the pathogenesis of epilepsy. [ABSTRACT FROM AUTHOR]

The etiology of Autism Spectrum Disorders (ASDs) as severe neurodevelopmental ailments is not known. However, several evidences point to dysregulation of immune system as an underlying cause of ASD. In the present study we evaluated the mRNA expression levels of TNF-α, TGF-β, IFN-γ, CXCL8, IL-1β, IL-2, 1L-4, IL-6, IL-17 in whole blood samples of 30 ASD patients and 41 age and sex-matched healthy subjects with means of real-time PCR. TNF-α, IL-6 and IL-17 have been shown to be significantly up-regulated in ASD patients compared with healthy subjects (P < 0.0001, P = 0.001 and P < 0.0001 respectively). IL-2 has been shown to be significantly down-regulated in total ASD patients (P < 0.0001). No significant difference has been found in expression levels of other cytokines between patients and healthy subjects. The present study provides further evidences for dysregulation of immune response in ASD patients. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) and Neuro-Behçet’s Disease (NBD) are two recurrent disorders affecting the central nervous system (CNS) by causing inflammation and irreversible damage. Inaugural clinical symptoms for both diseases might be very similar and definitive diagnosis could be delayed. The present study aimed to find out possible differences at early stages in the transcription factors/cytokines expression profiles in blood and cerebrospinal fluid (CSF) of MS and NBD patients which could be useful discriminative markers. Cytokines and transcription factors related to Th1, Th2, Th17 and T regulatory populations were studied by quantitative RT-PCR simultaneously in PBMCs and CSF, from 40 patients presenting a first episode of clinical features related to CNS inflammation and 22 controls with non inflammatory neurological diseases enrolled mainly for severe headache. The follow up of 12 months did allow a definitive diagnosis of remitting relapsing MS (RRMS) in 21 patients and of NBD in the other 19 among those with CNS inflammation compared to controls. In initial blood samples, T-bet was significantly increased in NBD patients only while IFN-γ was elevated in patients who evolved into RRMS or NBD. IL-17a, GATA-3 and IL-4 were significantly lower in RRMS patients than in the NBD group. In initial CSF samples, ROR-γt, IL-17a and IFN-γ were significantly elevated in patients compared to controls. The most striking finding was the significant increase of CSF IL-10 that we did observe in NBD patients only. Thus, we propose CSF IL-10 as a predictive marker to help clinicians discriminating between these two neurological disorders. [ABSTRACT FROM AUTHOR]

Guillain Barré Syndrome (GBS) is a severe disorder of the peripheral nervous system with an inadequately known etiopathology. It is a post infectious immune mediated disorder, characterized by autoantibody production, complement activation as well as T reactivity against gangliosides. However, the precise etiopathogenesis remains poorly understood in a majority of the patients. Th17 cells, a recently identified lineage of Th cells have emerged as a predominant inducer of autoimmunity and inflammation in various immunological disorders. Pathobiological role of Th17 pathway is also becoming increasingly apparent in the nervous system disorders. Two cytokines, such as IL-23, known to determine the pathogenic potential of Th17 cells and IL-17, a prototype effector cytokine of Th17 pathway can form IL-23/IL-17 immune axis. Aberrant functioning of this immune axis has been implicated in many autoimmune diseases. Therapeutic strategies that potentially target this immune axis have shown encouraging results in diseases with immunological underpinnings. Preliminary data obtained both from animal and clinical studies indicate a possible role of this immune axis in GBS. Herein, we explore and highlight the relevance and functional implications of IL-23/IL-17 immune axis in GBS. Understanding this immune axis may shed important insights into the etiology and treatment of GBS. [ABSTRACT FROM AUTHOR]

Background Although several studies suggest a possible link between dyslipidemia and atopy, literature findings are still unclear. Objective The aim of the study was to investigate the relationship between dyslipidemia and atopy in a pediatric population affected by dyslipidemia or dyslipidemia/atopic predisposition. Materials and methods Children with dyslipidemia, dyslipidemia and atopy as well as healthy children were recruited. Serum total IgE, IL-10, IL-17, and IL-23 levels as well as fasting lipid values (total cholesterol, LDL, HDL and triglycerides) were performed on all enrolled children. Results The present study evaluated 23 patients affected by dyslipidemia, 26 patients affected by atopy and dyslipidemia and, 22 healthy children. Serum total IgE levels significantly related also with serum cholesterol levels: positively with total cholesterol (p < 0.05), LDL (p < 0.05), and tryglicerides (p < 0.001), but negatively with HDL (p < 0.05). Serum levels of IL-10 were lower in children with atopy and dyslipidemia than patients with dyslipidemia (p < 0.001). Serum IL-10 levels significantly related also with serum cholesterol levels: negatively with total cholesterol (p < 0.001), LDL (p < 0.05), and triglycerides (p < 0.05), but positively with HDL (p < 0.05). Serum IL-17 and IL-23 levels showed the same trend. They were significantly higher in children with atopy and dyslipidemia than patients with dyslipidemia (p < 0.001). In particular, serum IL-17 and IL-23 values positively correlated with serum total IgE levels (p < 0.05); serum total cholesterol levels (p < 0.001); serum LDL levels (p < 0.001); serum triglycerides levels (p < 0.05). Although not statistically significant, an inverse correlation has been noted between serum IL-17, IL-23 and HDL levels. Conclusions These findings support the notion that dyslipidemia and atopic predisposition share the same immune pathways as well as they offer new insights in the complex crosstalk between hyperlipidemia and atopy. [ABSTRACT FROM AUTHOR]

IL-23 and IL-17 are pro-inflammatory cytokines. IL-23 is secreted by activated macrophages and dendritic cells, while IL-17 by Th17 cells. Serum IL-23 and IL-17 are known to be elevated in numerous inflammatory diseases including neurodegenerative diseases. The role of serum IL-23 and IL-17 in aneurysmal subarachnoid hemorrhage (aSAH) has still not been investigated. The present work investigates the serum IL-23 and IL-17 levels and their association with post hemorrhagic complications and clinical outcome in patients with aSAH. Methods In this study, 80 patients with aSAH (Hunt and Hess grade I-V) were prospectively recruited. We enrolled 24 control patients with lumbar spinal stenosis. Peripheral venous blood was withdrawn from controls and from aSAH patients at day 1 and day 7, allowed to clot and centrifuged to obtain serum. Enzyme linked immunoassay kits were employed to quantify the serum levels of IL-23 and IL-17 by applying 50 µL of serum samples. Post hemorrhagic complications and clinical outcome were documented prospectively from patient’s hospital record. Results Serum IL-23 and IL-17 levels were significantly elevated in aSAH patients at day 1 and day 7 (n = 80) as compared to control patients (n = 24). Further analysis after dichotomy of patients who suffered from post hemorrhagic complications including cerebral vasospasm, chronic hydrocephalus, seizures, cerebral ischemia, delayed neurological deficits showed differential correlations with different post hemorrhagic complications (Table 1). Serum IL-23 and IL-17 levels did not correlate with clinical outcome. Conclusion Serum IL-23 and IL-17 levels were elevated in patients with aSAH showing upregulation of IL-23/IL-17 inflammatory axis after aSAH. Serum IL-23 and IL-17 showed differential correlations with post hemorrhagic complications and no correlation with clinical outcome. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is assumed to be caused by genetic and environmental factors that interact together in promoting intestinal immune dysregulation where cytokines have validated role. However, the underlying intimate mechanisms in the human IBD involving cytokines still needs to be supplemented especially in the clinical context. The aim of this study was to investigate the expression of some inflammatory and regulatory cytokines (IL-17A, IL-23, IL-6, TGFβ1, and IL-10) as well as of the transcription factor FoxP3 in mucosal samples of IBD and non-IBD patients. We assessed the mRNA relative quantities (RQ) of the above-mentioned cytokines and the transcription factor FoxP3 in paired colonic samples (inflamed and adjacent normal mucosa) from 37 patients with IBD and in normal mucosal tissue in 12 persons without IBD by performing a qRT-PCR assay and tested the protein levels of target cytokines in serum samples. The patients were divided into three groups: without any therapy (n = 10), on 5-ASA (n = 11) and on immunosuppressants (Azathioprine ± 5-ASA/corticosteroids) (n = 16) in order to compare the RQ values for each therapeutic group. All investigated genes were found upregulated in the inflamed mucosa of IBD patients in the following order: IL-6 > FoxP3 > TGFβ1 > IL-23 > IL-17A > IL-10. We also observed that the gene expression of FoxP3 and IL-6 were substantially higher in the inflamed mucosal tissue of the IBD patients than the adjacent normal mucosa (p = 0.035, p = 0.03 respectively). Differences between higher mRNA expression of FoxP3 and IL-6 in inflamed tissue were considered significant in patients with ulcerative colitis (UC) (p = 0.011, p = 0.000 respectively) and with Crohn’s disease (CD) (p = 0.008, p = 0.000 respectively) in comparison to the normal mucosa of non-IBD persons and we found increased TGFβ1 in CD patients alone (p = 0.041). Furthermore, IL-6 and TGFβ1 were overexpressed (RQ > 10) in non-inflamed mucosa from IBD patients compared to the normal mucosa from the controls. When we compared the gene expression for paired mucosa in the immunosuppressive treated group with the 5-ASA treated group we observed opposite changes in IL-6 and TGFβ1 expression. Additionally, we found higher serum levels of IL-23 (p = 0.008), TGFβ1 and IL-6 in IBD patients compared to non-IBD patients. The obtained specific expression profile consisting of IL-6, TGFβ1, IL-10 and FoxP3 may represent a transcriptional hallmark for IBD. Furthermore, we found that treatment with immunosuppressive therapy was more beneficial for driving cytokine expression to restore immune regulation in patients with IBD, unlike the 5-ASA therapy. [ABSTRACT FROM AUTHOR]

The CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor is activated by multiple inflammatory stimuli, including IL-17 and LPS, and C/EBPβ itself regulates numerous genes involved in inflammation. However, the role of C/EBPβ in driving autoimmunity is not well understood. Here, we demonstrate that Cebpb −/− mice are resistant to EAE. Cebpb −/− mice exhibited reduced lymphocyte and APC infiltration into CNS following EAE induction. Furthermore, MOG-induced Th17 cytokine production was impaired in draining LN, indicating defects in Th17 cell priming. In vitro Th17 polarization studies indicated that T cell responses are not inherently defective, instead supporting the known roles for C/EBPβ in myeloid lineage cell activation as the likely mechanism for defective Th17 priming in vivo. However, we did uncover an unexpected role for C/EBPβ in regulating ll23r expression in APCs. ChIP assays confirmed that C/EBPβ binds directly to the Il23r gene promoter in dendritic cells and Th17 cells. These data establish C/EBPβ as a key driver of autoimmune inflammation in EAE, and propose a novel role for C/EBPβ in regulation of IL-23R expression. [ABSTRACT FROM AUTHOR]

The role of adaptive immune cytokines in the pathogenesis of type-1 Diabetes Mellitus (T1DM) is well known. Even though reports on the serum levels of both Th-1 and Th-2 cytokines are available, those on newly described T cell cytokines such as IL-17, IL-33 and IL-9 in T1DM are scarce. We therefore measured the serum levels of both T cell polarizing (IL-33 and IL-12) and T cell effector (IFN-γ, IL-4, IL-10, IL-17 and IL-9) cytokines in T1DM subjects with and without microvascular (retinopathy and nephropathy) complications (MVC). All the tested cytokines were significantly elevated in T1DM subjects except for IFN-γ (which failed to attain statistical significance) with no significant difference between those with and without MVC. From the serum cytokine analysis, no apparent Th polarization could be determined for the T1DM subjects. [ABSTRACT FROM AUTHOR]

Different T cell subsets have been implicated in the pathogenesis of glomerulonephritis. Several lines of evidence indicate the recently identified interleukin-17 (IL-17)-producing T cells (Th17 cells) to be involved in the renal inflammatory cascade associated with glomerulonephritis. In this review we outline different forms of glomerulonephritis and the contribution of the Th17/IL-17-axis in mediating the downstream effects and pathology associated with the disease. Learning more about the Th17/IL-17-axis can help to develop promising therapeutic strategy for the treatment of various forms of glomerulonephritis. [ABSTRACT FROM AUTHOR]

Aim To determine the role of IL-17 and IL-6 in the pathogenesis of SLE as biomarkers of disease activity and predictors of remission and outcome of therapy in patients with active lupus nephritis. Methods The study was carried out on 72 SLE female patients and 70 sex- and age-matched normal healthy subjects as controls. SLE disease activity was assessed in all patients with (SLEDAI-2k scores). Plasma levels of IL-6, and IL-17 were measured by enzyme linked immunosorbent assay and their levels were correlated with clinical manifestations of the disease and (SLEDAI-2k). ROC curve analysis was performed to determine the validity of both cytokines in prediction of activity and remission of active lupus nephritis. Results SLE patients were found to have significantly higher levels of IL-17 ( p < 0.001) and IL-6 ( p < 0.001), in relation to normal subjects. Active group of patients had higher levels of both cytokines than the inactive one ( P < 0.001). Elevated serum levels of both cytokines were associated with active lupus nephritis, anemia and positively correlated with SLEDAI-2k scores ( P = 0.025 for IL-17 and P < 0.001 for IL-6). There was a significant positive correlation between IL-6 and IL-17 serum concentrations during periods of disease activity ( r = 0.497, P = 0.005) as well as during remission ( r = 0.662, P < 0.001). ROC curve analysis for IL-6 and IL-17, as predictor of disease activity reviled, optimal cutoff level of 12.3 pg/ml and 19.7 pg/ml, with AUC = 0.93, and 0.95, for both cytokines respectively, while as predictors of remission of active lupus nephritis, provide a cutoff value of IL-6 at 20.8 pg/ml, with AUC 0.80, and a cutoff value of IL-17 at 27.0 pg/ml, with AUC 0.82. Conclusion In conjunction with their major role in pathogenesis of SLE, baseline serum levels of IL-6 and IL-17 can be used as sensitive biomarkers for disease activity, as well as predictors of remission of lupus nephritis. [ABSTRACT FROM AUTHOR]

Background The overall immunopathology of the T-helper cell (Th)-17 immune response has been implicated in various inflammatory diseases including pulmonary inflammation; however its potential role in acute respiratory distress syndrome (ARDS) is not defined. This study aimed to evaluate the Th-17 response in bronchoalveolar lavage fluid (BALF) and blood and from trauma patients with pulmonary complications. Methods A total of 21 severely injured intensive care unit (ICU) subjects, who were mechanically ventilated and undergoing bronchoscopy, were enrolled. BALF and blood were collected and analyzed for Th-1 (interferon [IFN]γ), Th-2 (interleukin [IL]-4, -10), Th-17 (IL-17A, -17F, -22, 23) and pro-inflammatory (IL-1β, IL-6, tumor necrosis factor [TNF]α) cytokine levels. Results Significant levels of the Th-17 cytokines IL-17A, -17F and -21 and IL-6 (which can be classified as a Th-17 cytokine) were observed in the BALF of all subjects. There were no significant differences in Th-17 cytokines between those subjects with ARDS and those without, with the exception of plasma and BALF IL-6, which was markedly greater in ARDS subjects, as compared with controls and non-ARDS subjects. Conclusions Trauma patients with pulmonary complications exhibited a significant Th-17 response in the lung and blood, suggesting that this pro-inflammatory milieu may be a contributing factor to such complications. [ABSTRACT FROM AUTHOR]

CD4 + CD25 + Foxp3 + regulatory cells (T regs ) are a special lineage of cells central in the maintenance of immune homeostasis, and are targeted for human immunotherapy. They are conventionally associated with the production of classical anti-inflammatory cytokines such as IL-10, TGF-β and IL-35, consistent to their anti-inflammatory functions. However, emerging evidence show that they also express effector cytokines such as IFN-γ and IL-17A under inflammatory conditions. While some studies reveal that these pro-inflammatory cytokine producing Foxp3 + regulatory cells retain their suppressive ability, others believe that these cells are dys-regulated and are associated with perpetuation of immunopathology. Therefore the development of these cells may challenge the efficacy of human T reg therapy. Mechanistically, toll-like receptor (TLR) ligands and the pro-inflammatory cytokine milieu have been shown to play important roles in the induction of effector cytokines in T regs . Here we review the mechanisms of development and the possible functions of pro-inflammatory cytokine producing Foxp3+ T regs . [ABSTRACT FROM AUTHOR]

Patients with systemic autoimmune diseases exhibit a higher incidence of atherosclerosis. Conversely, hyperlipidemia has been known to accelerate autoimmune diseases in humans as well as in experimental animal. How atherosclerosis impacts autoimmunity remains poorly understood. Importantly, recent studies showed that several pro-atherogenic factors including cholesterol, oxidized low-density lipoprotein and fatty acids regulate the production of IL-17 and IL-17-promoting cytokines from innate and adaptive immune cells. Given that IL-17 is associated with a number of autoimmune diseases in humans, dissecting the mechanisms beyond the mutual regulation of pro-atherogenic factors and IL-17 might provide a novel pathophysiology between atherosclerosis and autoimmune diseases. In this review, we discuss our current understanding related to the role of pro-atherogenic factors in IL-17 production and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Acquired aplastic anemia (AA) is an immune mediated bone marrow failure syndrome which is associated with impaired T-cell immune responses. In this work we investigated the role of Th17 immune response in AA. Our results showed that the absolute numbers of circulating IL-17-producing CD4 + T cells and CD4 + CD161 + CCR6 + cells, the blood plasma level of IL-17, and the expression level of Th17 lineage-specifying transcription factor RORC in circulating CD4 + T cells, were not increased in AA. These results suggest that Th17 immune response may not play an important role in the pathogenesis of AA. [ABSTRACT FROM AUTHOR]

Over the past few years, the importance of Interleukin (IL)-17 and T helper (Th)17 cells in the pathology of Rheumatoid Arthritis (RA) has become apparent. RA is a systemic autoimmune disease that affects up to 1% of the population worldwide. It is characterized by an inflamed, hyperplastic synovium with pannus formation, leading to bone and cartilage destruction in the joints. By the production of effector cytokines like IL-17 and IL-22, the T helper 17 subset protects the host against bacterial and fungal infections, but it can also promote the development of various autoimmune diseases like RA. Hence, the Th17 pathway recently became a very interesting target in RA treatment. Up to now, several therapies targeting the Th17 cells or its effector cytokines have been tested, or are currently under investigation. This review clarifies the role of Th17 cells and its cytokines in the pathogenesis of RA, and provides an overview of the clinical trials using immunotherapy to target this particular T helper subset or the two main effector cytokines by which the Th17 cells exert their function, IL-17 and IL-22. [ABSTRACT FROM AUTHOR]

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and cancer predisposition. Several studies show alterations of the immunological status of FA patients including defects in peripheral blood lymphocyte subsets, serum immunoglobulin levels, and inflammatory cytokines. However scanty information is available on the response of FA cells to specific infectious antigens. In this work we examined the response of FA cells to different immunological stimuli and found a defective response of IL-1β, TNF-α and IL-17 to Candida albicans stimulation thus pointing to a potentially impaired response to fungal infections of FA patients. [ABSTRACT FROM AUTHOR]

The role of inflammation in both diabetes and diabetic kidney disease (DKD) is becoming more widely accepted. However, the role of recently characterized T cell cytokines interleukin (IL)-9 and IL-17 in diabetes and especially DKD is less well studied. Transforming growth factor beta (TGF-β) controls the secretion of both of these cytokines. In this study, we estimated the levels of IL-9, IL-17, and TGF-β in the serum of subjects with normal glucose tolerance (NGT = 88) and subjects with type 2 diabetes without (diabetes mellitus (DM) = 65) and with DKD (DKD = 97) using enzyme-linked immunosorbent assay (ELISA), and we correlated these levels with the clinical risk factors of diabetes and DKD. IL-17 levels showed a serial decline and TGF-β levels showed a serial increase from NGT to DM to DKD ( p < 0.001). However, the IL-9 levels were significantly reduced in the DM group compared to the NGT and DKD group ( p < 0.001). While TGF-β and IL-17 showed a positive and negative correlation, respectively, with fasting and postprandial glucose levels and glycated hemoglobin (HbA1c), IL-9 showed positive correlation with urea and microalbuminuria. Apart from pro-inflammatory cytokines, T helper (Th) cytokines might play an important role in insulin resistance and DKD. [ABSTRACT FROM AUTHOR]

The emergence of Th17 cells as a unique sub-population of CD4 + T cells has revolutionized the current understanding of adaptive immune system and autoimmune diseases. Th17 cells are characterized by the expression of effector cytokines IL-17A, IL-17F, IL-21 and IL-22, and lineage specific transcription factor ROR-C in human and ROR-γt in mice. Generation and differentiation of Th17 cells from naive CD4 + T cells is driven by transforming growth factor (TGF)-β, IL-6, IL-23, IL-1β and IL-21. Recent studies suggest that the pathogenicity of Th17 cells is determined by the presence of IL-23 and TGF-β3 in local micro-environment. Emerging reports highlight the importance of T-helper cell plasticity in pathogenesis of various autoimmune diseases. Th17 cells exhibit significant plasticity and converted to Th1-like cells under pathogenic conditions. Albeit growing body of evidences stating a pathogenic role for Th17 cells in autoimmune diabetes, conflicting reports also state an indifferent or protective role for Th17 cells. The operating mechanisms modulating Th17 immune response in autoimmune diabetes remain elusive. This review discusses recent advances in the understanding of transcriptional and post-transcriptional mechanisms of Th17 polarization, factors influencing pathogenicity of Th17 cells, molecular mechanisms of Th17/Th1 and Treg/Th17 plasticity and implications of these phenomena in autoimmune diabetes. [ABSTRACT FROM AUTHOR]

Background: Cytokines are important factors determining the outcome of transplantation. Host ability in cytokine production may be affected by cytokine genes polymorphisms. The aim of the present study was to investigate the effect of IL-17 gene polymorphisms on outcome of Hematopoietic stem cell transplantation. Materials and methods: A total of 60 bone marrow recipients were included in this study. Twenty-five recipients (41.66%) underwent a GVHD. IL-17 gene polymorphisms were evaluated by PCR-RFLP method and the serum levels were also checked by ELISA. Results: No significant differences in distribution of the IL-17(A/G) (rs3819025) genotypes and alleles were observed between two groups. But, IL-17 (A/G, -197) GG genotype was found to be significantly higher in GVHD group compared to those of non-GVHD group (P=0.04). Interestingly, after stratification of patients according severity of GVHD, IL-17 (rs3819025) G allele was remained significantly higher in GVHD grade (0-I) group compared to those of grade (II-IV) group (P=0.05). In addition, after categorization of patients according to their sex, IL-17-197 GG genotype showed a significant association with non-GVHD in male patients (P=0.05). IL-17 serum levels did not show any significant difference between GVHD and non GVHD groups. Conclusion: Results indicated that IL-17197 GG genotype, G allele of (rs3819025) and its serum level have predictive values for severity of GVHD. Also, IL-17-197 GG genotype is a sex dependent genetic risk factor for development of GVHD, but this subject need to be studied in different population. [ABSTRACT FROM AUTHOR]

Highlights: [•] IL-23, IL-17 mRNA and their receptors mRNA altered in the PBC patients. [•] Increased serum IL-23 and IL-17 in PBC were correlated with clinical stages and GGT. [•] IL-23+cells and IL-17+cells accumulate in the livers of PBC patients. [•] IL-23 and IL-17 can serve as the indices for clinical monitoring of PBC. [ABSTRACT FROM AUTHOR]

Highlights: [•] IL-17A G-152A SNP, rs2275913, influences susceptibility to pulmonary tuberculosis. [•] -152G allele and GG genotype are associated with pulmonary tuberculosis. [•] G-152A polymorphism is not related neither with serum IL-17 levels nor with ex vivo IL-17 production. [ABSTRACT FROM AUTHOR]

Highlights: [•] Pre-treatment with low dose LPS offers survival benefit after challenge with a lethal dose of LPS. [•] Stimulated splenocyte release of pro-inflammatory cytokines is decreased and of IL-10 is increased. [•] LPS tolerance increases apoptosis of lymphocytes and splenocytes. [•] LPS tolerance up-regulated TREM1 expression of TREM-1 on monocytes and neutrophils. [•] LPS tolerance was accompanied by survival benefit after E. coli peritonitis. [ABSTRACT FROM AUTHOR]

Abstract: IL-17 is an inflammatory cytokine associated with anti-microbial host defense and pathogenesis of autoimmune diseases. Obesity is considered to be an inflammatory condition, but how cytokines and fat metabolism are interconnected remains poorly understood. Mesenchymal stem cells can differentiate into adipocytes, which serve as depots for stored fat. Despite the pro-inflammatory properties of IL-17, both IL-17- and IL-17RA-deficient mice are overweight. Consistently, IL-17 suppresses maturation of cells with adipogenic potential. However, the mechanism underlying IL-17-mediated inhibition is not defined. In this study, we addressed this question by evaluating the impact of IL-17 on a variety of transcription factors (TFs) that control adipogenesis, using 3T3-L1 cells to model adipocyte differentiation. Surprisingly, IL-17 does not suppress adipogenesis via C/EBPβ and C/EBPδ, TFs often considered to be central regulators of adipogenesis. Rather, IL-17 suppresses expression of several pro-adipogenic TFs, including PPARγ and C/EBPα. Moreover, we found that IL-17 regulates expression of several members of the Krüppel-like family (KLF). Specifically, IL-17 suppresses KLF15, a pro-adipogenic TF, and enhances expression of KLF2 and KLF3, which are anti-adipogenic. Thus, IL-17 suppresses adipogenesis at least in part through the combined effects of TFs that regulate adipocyte differentiation. [Copyright &y& Elsevier]

Abstract: Psoriasis is a chronic, inflammatory skin disease with many associated co-morbidities including diabetes, hypertension, obesity, psoriatic arthritis, and cardiovascular disease. It has long been known that psoriasis is a T cell-mediate disease and recent findings further demonstrate the important roles of the Th17 and Th22 arms of the immune system in the pathogenesis of psoriasis. Our understanding of this disease has progressed greatly and agents that target the cytokines involved in disease activity are under development or currently being used to treat psoriasis. A comprehensive review of the literature for cytokine-targeted therapies, their safety concerns, and efficacy in psoriasis are discussed here. [Copyright &y& Elsevier]

Abstract: Increased interleukin (IL)-17 and IL-23 levels exist in the gingival tissue of periodontitis patients, but the precise molecular mechanisms that regulate IL-17 and IL-23 production remain unknown. The aim of this study was to explore the role of SIRT1 signaling on Porphyromonas gingivalis lipopolysaccharide (LPS)-induced IL-17 and IL-23 production in human periodontal ligament cells (hPDLCs). IL-17 and IL-23 production was significantly increased in LPS-treated cells. LPS treatment also led to the upregulation of SIRT1 mRNA and protein expression. LPS-induced IL-17 and IL-23 upregulation was attenuated by pretreatment with inhibitors of phosphoinositide 3-kinase (PI3K), p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase (MAPK), and NF-κB, as well as neutralizing antibodies against Toll-like receptors (TLRs) 2 and 4. Sirtinol treatment (a known SIRT1 inhibitor) or SIRT1 knockdown by small interfering RNA blocked LPS-stimulated IL-17 and IL-23 expression. Further investigation showed that LPS decreased osteoblast markers (i.e., ALP, OPN, and BSP) and concomitantly increased osteoclast markers (i.e., RANKL and M-CSF). This response was attenuated by inhibitors of the PI3K, p38, ERK, JNK, NF-κB, and SIRT1 pathways. These findings, for the first time, suggest that human periodontopathogen P. gingivalis LPS is implicated in periodontal disease bone destruction and may mediate IL-17 and IL-23 release from hPDLCs. This process is dependent, at least in part, on SIRT1-Akt/PI3K-MAPK-NF-κB signaling. [Copyright &y& Elsevier]

Abstract: The overexpression of osteopontin is associated with various inflammatory liver diseases. Interestingly, each of these diseases is also associated with IL-17 expression. Therefore, we sought to determine whether there is any mechanistic link between osteopontin and IL-17. Herein we show that IL-17 and osteopontin levels were significantly increased in patients with chronic hepatitis B. We found that IL-17 and osteopontin levels increased similarly in mice with concanavalin A-induced hepatitis. Both osteopontin- and IL-17-deficient mice were resistant to concanavalin A-induced hepatic injury. In addition, osteopontin markedly induced IL-17 expression by leukocytes (from humans and mice). This effect could be blocked by a specific antibody against osteopontin. β3 integrin (one of the osteopontin receptors) was critically involved in the induction of IL-17 production by osteopontin. Osteopontin-induced IL-17 expression was mediated through the p38, JNK, and NF-κB pathways. These findings suggest that osteopontin regulates IL-17 production during the pathogenesis of hepatitis and provide new evidence for the critical roles of osteopontin and IL-17 in hepatitis. [Copyright &y& Elsevier]

Abstract: Th17 cells play a crucial role in host immune response. We examined the role of Th17 cells in HIV-1 ‘subtype-C’ infection and report that HIV-1 specific Th17 cells are induced in early infection and slow progressors but are significantly reduced at late stage of infection. There was a further decline in Th17 cells in late stage subjects with gastrointestinal infections. Additionally, we observed expanded population of IL-21 (needed for Th17 population expansion) producing CD4 T cells in early and slow progressors compared to subjects with late stage infection. A significant positive correlation existed between virus specific IL-17 and IL-21 producing CD4 T cells suggesting that HIV-1 infection induces a demand for Th17 cells. A significant negative correlation between virus specific Th17 cells and HIV-1 plasma viral load (pVL) was also observed, indicating a gradual loss of Th17 cells with HIV-1 disease progression. [Copyright &y& Elsevier]

Abstract: In the veterinary field, only limited information is available about interleukin-17A (IL-17), despite the fact that this cytokine plays an important role during pro-inflammatory immune responses and induces the production of chemotactic factors for neutrophils. The aim of this study was to characterize porcine IL-17-producing cells. We tested the cross-reactivity of five anti-human IL-17 monoclonal antibodies because such antibodies against porcine IL-17 are currently unavailable. Whole blood cells (WBCs) were stimulated with phorbol-myristate-acetate (PMA) and ionomycin and subsequently analyzed by flow cytometry. The antibody clone SCPL1362 was found to cross-react with porcine IL-17, whereas the other four antibodies tested did not recognize this cytokine. Using this antibody, we characterized porcine WBC-secreting IL-17 after PMA and ionomycin stimulation. All IL-17-producing WBCs were positive for the T lymphocyte marker CD3. Myeloid cells (CD172α+) and B lymphocytes (CD79α+) were IL-17 negative. The major subset of IL-17 positive T lymphocytes was the CD4+ lymphocytes (about 60% of all IL-17 positive WBCs). The remaining IL-17 positive WBCs were γδTCR+ lymphocytes. CD8 positive and CD8 negative cells were found within both CD4+ and γδTCR+ cells producing the cytokine. Moreover, IL-17 positive cells were mostly CD45RA negative, therefore activated cells or memory cells. Flow cytometry data were confirmed using sorted cells. Both sorted CD4+ and γδTCR+ cells produced IL-17 at mRNA level after PMA and ionomycin stimulation while double negative CD4−γδTCR− cells were negative for IL-17. We can conclude that only two subpopulations of porcine WBCs are sources of IL-17 after non-specific stimulation: CD3+CD4+ and CD3+γδTCR+. [Copyright &y& Elsevier]

Abstract: Focusing on the first 3weeks of life, this study examined the mRNA transcript development of different Th-type cytokines in foals in response to Rhodococcus equi infection in vitro. Results demonstrated the significant up-regulation in expression of Th1-, Th2-, and Th17-type cytokines (IFN-γ, IL-4, IL-6, IL-8, IL-12p35, IL-12p40, IL-17, IL-23p19, and TNF-α) in R. equi infection of bronchial alveolar lavage (BAL) cells of 10-day-old foals. Consequently, signature cytokines of 3 Th cell types, IFN-γ (Th1), IL-4 (Th2), and IL-17 (Th17), were used to compare temporal response patterns of circulating peripheral blood mononuclear cells (PBMCs) to stimulation with R. equi. Foals responded to R. equi stimulation by producing similar amounts of IFN-γ mRNA transcripts from birth through 3weeks of age, suggesting an absence of age-related impairment in Th1-type cytokine response to R. equi during the first 3weeks of life. It remains debatable whether this Th1 response to R. equi in foals⩽3weeks of age is generally immature relative to older foals or adult horses. IL-4 expression by R. equi-stimulated PBMCs was significantly decreased at birth, and IL-17 expression was relatively reduced during the first week of life. Among all cytokines studied, IL-17 mRNA transcripts were induced with the highest magnitude of fold-change both in BAL cells and in PBMCs. Under the conditions studied, in vivo administration of a CpG failed to modulate the Th1-, Th2-, and Th17-type cytokine expression patterns in PBMCs. [Copyright &y& Elsevier]

Abstract: The interleukin (IL)-1 cyokine family plays a vital role in inflammatory responses during infection and in autoimmune diseases. The pro-inflammatory cytokines, IL-1β and IL-18 are members of the IL-1 family that require cleavage by caspase-1 in the inflammasome to generate the mature active cytokines. Cells of the innate immune system, including γδ T cells and invariant natural killer T (iNKT) cells respond rapidly to invading pathogens by producing inflammatory cytokines, such as IFN-γ and IL-17. IL-1β or IL-18 in combination with IL-23 can induce IL-17 production by γδ T cells without T cell receptor (TCR) engagement. IL-1β and IL-23 can also synergize to induce IL-17 production by iNKT cells. Furthermore, CD4+ αβ effector memory T cells secrete IL-17 in response to IL-23 in combination with either IL-1β or IL-18, in the absence of any TCR stimulation. The early IL-17 produced by innate cells induces recruitment of neutrophils to the site of infection, stimulates local epithelial cells to secrete anti-microbial proteins, such as lipocalins and calgranulins, induces production of structural proteins important in tight junction stability, and promotes production of matrix metalloproteinases. Caspase-1 processed IL-1 family cytokines therefore play a vital role in the innate immune response and induction of IL-17 from innate immune cells which functions to fight infections and promote autoimmunity. [Copyright &y& Elsevier]

Abstract: Syngeneic graft-versus-host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow (BM) and treatment with a 21day course of the immunosuppressive agent cyclosporine A (CsA). Clinical symptoms of SGVHD appear 2–3weeks post-CsA with inflammation occurring in the colon and liver. Previously we have demonstrated that CD4+ T cells and a T helper cell type 1 cytokine response (TH1) are involved in the development of SGVHD associated intestinal inflammation. Studies have recently discovered an additional T cell lineage that produces IL-17 and is termed TH17. It has been suggested that inflammatory bowel disease is a result of a TH17 response rather than a TH1 response. This study was designed to investigate TH17 involvement in SGVHD-associated colitis. Following induction of SGVHD, the levels of TH17 and TH1 cytokine mRNA and protein were measured in control and SGVHD animals. In vivo cytokine neutralization was performed to determine the role of the prototypic TH17 cytokine, IL-17, in the disease process. We found that during CsA-induced murine SGVHD there was an increase in both TH17 and TH1 mRNA and cytokines within the colons of diseased mice. The administration of an anti-mouse IL-17A mAb did not alter the course of disease. However, neutralization of IL-17A resulted in an increased production of IL-17F, a related family member, with an overlapping range of effector activities. These results demonstrate that in the pathophysiology of SGVHD, there is a redundancy in the TH17 effector molecules that mediate the development of SGVHD. [Copyright &y& Elsevier]

Abstract: Bacterial meningitis has a poor prognosis and neurologic complications. The present study aimed to investigate the cytokine/chemokine network in cerebrospinal fluid (CSF) from children with bacterial meningitis and aseptic meningitis. Interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-γ, tumor necrosis factor-α, granulocyte colony-stimulating factor, granulocyte monocyte colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β, were measured simultaneously in CSF supernatants. We found that, IL-17 was significantly elevated in CSF with bacterial meningitis. We believe that IL-17 plays a key role in neutrophil infiltration into CSF and neuronal protection in bacterial meningitis. [Copyright &y& Elsevier]

Abstract: Discovery of the T-helper (Th) 17 cell lineage and functions in immune responses of mouse and man prompted us to investigate the role of transforming growth factor-beta (TGF-β) and interleukin (IL)-17 in innate resistance to murine schistosomiasis mansoni. Schistosoma mansoni-infected BALB/c and C57BL/6 mice were administered with recombinant TGF-β or mouse monoclonal antibody to TGF-β to evaluate the impact of this cytokine on host immune responses against lung-stage schistosomula, and subsequent effects on adult worm parameters. Developing schistosomula elicited increase in peripheral blood mononuclear cells (PBMC) mRNA expression and/or plasma levels of IL-4, IL-17, and interferon-gamma (IFN-γ), cytokines known to antagonize each other, resulting in impaired Th1/Th2, and Th17 immune responses and parasite evasion. Mice treated with TGF-β showed elevated PBMC mRNA expression of IL-6, IL-17, TGF-β, and TNF-α mRNA and increased IL-23 and IL-17 or TGF-β plasma levels, associated with significantly (P <0.02–<0.0001) lower S. mansoni adult worm burden compared to controls in both mouse strains, thus suggesting that TGF-β led to heightened Th17 responses that mediated resistance to the infection. Mice treated with antibody to TGF-β showed increase in PBMC mRNA expression and plasma levels of IL-4, IL-12p70, and IFN-γ, and significantly (P <0.02 and <0.0001) reduced worm burden and liver worm egg counts than untreated mice, indicating that Th1/Th2 immune responses were potentiated, resulting in significant innate resistance to schistosomiasis. The implications of these observations for schistosome immune evasion and vaccination were discussed. [Copyright &y& Elsevier]

Abstract: Th17 cells are critical in adaptive immunity and autoimmune disease. The polarized development of Th17, Th1 and Th2 cells is dependent on counterregulatory effects on each other. Whereas IFN-γ inhibits Th17 development, the effect of IL-17 in human Th1 development is not known. We report a novel negative regulatory role of IL-17 on IL-12Rβ2 expression associated with reduced IL-12 responsiveness. IL-17 decreased IL-12-induced IFN-γ expression in PBMC and developing Th1 cells, associated with a selective reduction in IL-12Rβ2, and not IL-23R, IL-12Rβ1 or T-bet. Counterregulatory effects of human Th17 on Th1 lineage cytokines may contribute to lineage divergence. In autoimmune disease, IL-17 may reinforce its own developmental programme by reducing IL-12 responsiveness, thus limiting inhibitory effects of IFN-γ on Th17 development. [Copyright &y& Elsevier]

Abstract: Although a notable amount of CCL20 is detectable in the synovial fluid of human rheumatoid arthritis (RA), its role in the pathogenesis of RA remains to be determined. IL-1β vigorously induced the production of CCL20 from FLSs of human RA and the production of CCL20 induced by TNF-α was partially attributed to a trace amount of IL-1β induced by TNF-α. Although IL-6 failed to induce CCL20, TNF-α-induced IL-6 enhanced the production of CCL20 in an autocrine/paracrine manner. To determine the role of CCL20 and its sole receptor CCR6 in the recruitment of mononuclear cells (MNCs) into the inflamed joint of RA, conditioned medium of IL-1β-stimulated FLSs was used in migration assays. The conditioned medium significantly recruited CCR6+ MNCs in a CCL20-dependent manner. The production of CCL20 induced by TNF-α and IL-1β was modified by helper-T-cell-derived cytokines. Interestingly, CCL20 enhanced the production of IL-6 coordinately with the stimulation of IL-17 but not with that of IFN-γ. These findings imply FLSs stimulated by proinflammatory cytokines recruit CCR6+ MNCs including IL-17-producing-helper T cells into the inflamed joint, leading to the enhancement of the production of CCL20, which chemokine and IL-17 coordinately induce proinflammatory cytokines. [Copyright &y& Elsevier]

• Inflammatory cytokines exert direct detrimental effects on human spermatozoa. • Interferon γ, IL-17A and IL-1β trigger sperm ROS production. • Interferon γ, IL-17A and IL-1β impair sperm motility and induce sperm apoptosis. Urogenital inflammation is a known cause of male infertility. Increased levels of inflammatory cytokines, leukocyte counts and oxidative stress are highly detrimental for sperm quality thus compromising male fertility. Although cytokines affect sperm by recruiting and activating leukocytes consequently inducing tissue inflammation and oxidative stress, scarce to absent data have been reported about the putative direct effects of inflammatory cytokines on spermatozoa. Herein, we analyzed whether IFNγ, IL-17A, IL-1β, and IL-8 can alter human sperm motility and viability per se. Fractions of viable and motile spermatozoa from normospermic healthy donors were in vitro incubated with recombinant human IFNγ, IL-17A, IL-1β or IL-8 and sperm ROS production, motility, viability and apoptosis were analyzed. Sperm exposed to different concentrations of IFNγ, IL-17A and IL-1β, or a combination of them, for either 1 or 3 h showed significantly increased levels of mitochondrial ROS production and reduced motility and viability with respect to sperm incubated with vehicle. Moreover, the exposure to IFNγ, IL-17A and IL-1β resulted in significantly higher levels of early and/or late apoptotic and/or necrotic spermatozoa. Interestingly, no significant differences in sperm motility, viability and apoptosis were observed in sperm incubated with the concentrations of IL-8 analyzed, for either 1 or 3 h, with respect to sperm incubated with vehicle. In conclusion, our results indicate that IFNγ, IL-17A and IL-1β per se impair sperm motility and decreases viability by triggering increased mitochondrial ROS production and inducing sperm apoptosis. Our results suggest that screening inflammatory cytokines in semen would be an additional helpful tool for the diagnostic workup of male infertility. [ABSTRACT FROM AUTHOR]

Abstract: The IL-17 cytokine family is composed of six members. IL-17F, discovered in 2001, recently has drawn increasing attention due to its greatest similarity to IL-17, a widely recognized inflammatory cytokine. The genes encoding IL-17 and IL-17F are localized in the same chromosomal region and are co-expressed by CD4+ and γδ T cells. IL-17F can be secreted as homodimers or heterodimers with IL-17. Similar to IL-17, IL-17F utilizes IL-17RA and IL-17RC as its receptor and employs Act1 and TRAF6 as its signal transducers to induce the expression of pro-inflammatory cytokines and chemokines in many different cell types. However, mice lacking either IL-17 or IL-17F exhibit distinct defects in experimental models of asthma and colitis. These results have laid the basis to understand the role of IL-17F in the pathogenesis of human diseases. [Copyright &y& Elsevier]

Abstract: Since the discovery of interferons over 50 years ago, efforts to understand the biochemistry, molecular biology and biological activities of cytokines have been intense and rewarding. Although there are several hundred cytokines and receptors currently recognized, they in fact fall into a fairly limited set of subfamilies (reviewed in [Ozaki K, Leonard WJ. Cytokine and cytokine receptor pleiotropy and redundancy. J Biol Chem 2002;277:29355–58 ; Shen F, Gaffen SL. Structure–function relationships in the IL-17 receptor: implications for signal transduction and therapy. Cytokine 2008;41:92–104 ). Within these families (and in some cases even outside them), cytokines share many structural and functional features that have provided a framework for understanding their biological activities and signal transduction mechanisms. This review will focus on interleukin (IL)-17, the founding member of the newest subclass of cytokines, which has received considerable attention in the last several years due to its central role in the Th17 system. [Copyright &y& Elsevier]

Abstract: Recent evidence from several studies indicated that IL-17-producing Th17 cells can represent the key effector cells in the induction and development of autoimmune disorders. Cyclosporine A (CsA) is a commonly used immunosuppressant to treat lots of autoimmune diseases including rheumatoid arthritis (RA). Here, we demonstrated that PBMCs and purified CD4+ T cells from healthy individuals and patients with RA could be induced to produce large amounts of IL-17 after stimulation with anti-CD3 plus anti-CD28 mAbs. Phenotypic analysis indicated that the majority of IL-17-producing cells were Th17 cells with memory phenotype. The addition of CsA into cell cultures significantly inhibited the IL-17 production by Th17 cells at protein and at mRNA levels. Compared to the PBMCs from normal individuals, PBMCs from the patients with RA produced higher levels of IL-17 that was also significantly inhibited by CsA both at protein and at mRNA levels. The mechanism might be the effect of CsA on the T cells activation because the expression of CD69 and CD25 molecules on T cells was markedly reduced in the presence of CsA. Taken together, these results demonstrated that CsA suppressed the IL-17 production and inhibited the Th17 cells differentiation from both healthy individuals and patients with RA. [Copyright &y& Elsevier]

Abstract: Inflammatory processes are implicated in gastric cancer development. In contrast, the role of inflammation and proinflammatory cytokines in established cancer remains to be clarified. We investigated the contribution of IL-17A versus IL-17F-mediated intracellular signalling pathways in human gastric adenocarcinoma AGS cells. IL-8 secretion was evaluated by ELISA, mitogen-activated protein kinase (MAPK) [4] Abbreviations: MAPK, mitogen-activated protein kinase; AP-1, activator protein 1; NFκB, nuclear factor kappa B; siRNA, small interfering RNA; H. pylori, Helicobacter pylori; RA, rheumatoid arthritis; PMN, polymorphonuclear leukocytes; ERK, extracellular signal-regulated kinases; JNK, c-Jun N-terminal kinases. 4 by Western blotting, and activator protein 1(AP-1) and nuclear factor kappa B (NFκB) by TransAM transcription factor assay or qRT-PCR. IL-17RA and IL-17RC inhibition were achieved by small interfering RNA (siRNA). IL-17A significantly induced activation of all three MAPK (ERK, p38 and JNK) and downstream transcription factors AP-1 and p65 NFκB. IL-17F was less potent but induced a significant activation of p65 NFκB. Consistently, IL-17A was more potent to induce IL-8 secretion than IL-17F. Inhibition of either IL-17RA or IL-17RC expression via siRNA led to near complete abrogation of IL-17A-mediated c-Jun and p65 activation. These data suggest that in gastric cancer, absence of either IL-17RA or IL-17RC can inhibit IL-17 responsiveness. Conversely, downstream of IL-17R binding, IL-17A and IL-17F induce key signal transduction pathways implicated in inflammation and carcinogenesis. IL-17A, and possibly IL-17F, may contribute to amplification and persistence of inflammatory processes implicated in inflammation-associated cancer. [Copyright &y& Elsevier]