Search

Abstract Background The improvement of colitis symptoms by treatment with IL‐12/23 p40 neutralizing antibody should increase the muscle mass and the function of the sarcopenia phenotype. Methods An experimental colitis model was induced by oral administration of 2% dextran sulfate sodium (DSS) for 7 days. During induction of colitis, IL‐12/23 p40 neutralizing antibody was injected twice on Days 3 and 5. The total body mass index was measured by dual‐energy X‐ray absorptiometry. The muscle function was measured by forelimb grip strength and fatigue running distance. The muscle fibre cross‐sectional area (CSA) was calculated after the transverse section and haematoxylin and eosin staining, and gene expression was confirmed by RT‐qPCR. Differentiated C2C12 cells were used as in vitro models and treated with recombinant IL12/23 proteins to mimic the enhanced cytokines in colitis. Results The symptoms of colitis were alleviated by injection of IL‐12/23 p40 neutralizing antibody compared with phosphate‐buffered saline (PBS), and the disease activity index score was significantly lower on Day 8 (0.0 ± 0.00 of cont. vs. 11.3 ± 0.9 of DSS + PBS, P

The oocytes of female mammals will undergo aging after ovulation, also known as postovulatory oocyte aging (POA). Until now, the mechanisms of POA have not been fully understood. Although studies have shown that cumulus cells accelerate POA over time, the exact relationship between the two is still unclear. In the study, by employing the methods of mouse cumulus cells and oocytes transcriptome sequencing and experimental verification, we revealed the unique characteristics of cumulus cells and oocytes through ligand–receptor interactions. The results indicate that cumulus cells activated NF-κB signaling in oocytes through the IL1–IL1R1 interaction. Furthermore, it promoted mitochondrial dysfunction, excessive ROS accumulation, and increased early apoptosis, ultimately leading to a decline in the oocyte quality and the appearance of POA. Our results indicate that cumulus cells have a role in accelerating POA, and this result lays a foundation for an in-depth understanding of the molecular mechanism of POA. Moreover, it provides clues for exploring the relationship between cumulus cells and oocytes. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is hallmarked as a silent progressive rheumatic disease of the whole joint. The accumulation of inflammatory and catabolic factors such as IL6, TNFα, and COX2 drives the OA pathophysiology into cartilage degradation, synovia inflammation, and bone destruction. There is no clinical available OA treatment. Although traditional ayurvedic medicine has been using Boswellia serrata extracts (BSE) as an antirheumatic treatment for a millennium, none of the BSE components have been clinically approved. Recently, β boswellic acid (BBA) has been shown to reduce in vivo OA-cartilage loss through an unknown mechanism. We used computational pharmacology, proteomics, transcriptomics, and metabolomics to present solid evidence of BBA therapeutic properties in mouse and primary human OA joint cells. Specifically, BBA binds to the innate immune receptor Toll-like Receptor 4 (TLR4) complex and inhibits both TLR4 and Interleukin 1 Receptor (IL1R) signaling in OA chondrocytes, osteoblasts, and synoviocytes. Moreover, BBA inhibition of TLR4/IL1R downregulated reactive oxygen species (ROS) synthesis and MAPK p38/NFκB, NLRP3, IFNαβ, TNF, and ECM-related pathways. Altogether, we present a solid bulk of evidence that BBA blocks OA innate immune responses and could be transferred into the clinic as an alimentary supplement or as a therapeutic tool after clinical trial evaluations. [ABSTRACT FROM AUTHOR]

Abstract Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a significant threat to global health. This virus affects the respiratory tract and usually leads to pneumonia in most patients and acute respiratory distress syndrome (ARDS) in 15% of cases. ARDS is one of the leading causes of death in patients with COVID-19 and is mainly triggered by elevated levels of pro-inflammatory cytokines, referred to as cytokine storm. Interleukins, such as interleukin-6 (1L-6), interleukin-1 (IL-1), interleukin-17 (IL-17), and tumor necrosis factor-alpha (TNF-α) play a very significant role in lung damage in ARDS patients through the impairments of the respiratory epithelium. Cytokine storm is defined as acute overproduction and uncontrolled release of pro-inflammatory markers, both locally and systemically. The eradication of COVID-19 is currently practically impossible, and there is no specific treatment for critically ill patients with COVID-19; however, suppressing the inflammatory response may be a possible strategy. In light of this, we review the efficacy of specific inhibitors of IL6, IL1, IL-17, and TNF-α for treating COVID-19-related infections to manage COVID-19 and improve the survival rate for patients suffering from severe conditions. Graphical Abstract

Objective: Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s sarcoma (KS) and Primary effusion lymphoma (PEL), which are usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin1 (IL1) family is a major mediator for inflammation response and has functional role in both innate and adaptive immunity. In contrast to the well-studied IL1 molecules, the activation and functional role of IL1 receptor/co-receptor and other related ligands, such as the IL1 receptor accessory protein (IL1RAP), in KSHV pathogenesis and tumorigenesis remain almost unknown. Methods: In the current study, a series of KSHV negative and positive primary or tumor cells, as well as AIDS-KS tumor samples from cohort HIV+ patients were used to compare and determine the activation status of IL1 signaling molecules, and their functional roles in KSHV pathogenesis. Results: We reported the high activation of multiple IL1 signaling molecules, including IL1, IL36, IL1R1, IL1RAP and IRAKs, during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV-related malignancies. Directly targeting these molecules especially IL1R1 and IL1RAP significantly impaired the survival and growth of KSHV+ tumor cells, as well as their colony formation on 3-D culture. Conclusion: Our data indicate the importance of IL1 signaling molecules in KSHV pathogenesis and tumorigenesis, which may represent attractive therapeutic targets against these virus-associated diseases. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) affects more than 300 million people worldwide and it is about to become the first disabling disease. OA is characterized by the progressive degradation of the articular cartilage but is a disease of the whole joint. Articular innate immune responses (IIR) associated with tissue degradation contribute to its progression. However, no treatment is available to block these IIRs. Through data text mining and computational pharmacology, we identified two clinical available drugs, naloxone, and thalidomide, with potential inhibitory properties on toll-like receptor 4 (TLR4), a major activator of these IIR. Proteome analysis confirmed that activation of this receptor or the IL1 receptor generated OA-like and gout-like proteomic changes in human primary chondrocytes. Both compounds were found to block TLR4 complex and inhibit TLR4 and IL1R-mediated IIR in OA chondrocytes, osteoblasts, and synoviocytes. Furthermore, naloxone and thalidomide inhibitory effects involved the downregulation of the NLRP3 inflammasome pathway, which is downstream of TLR4/IL1R signaling. We demonstrated that these compounds, within a therapeutic range of concentrations, exhibited anti-inflammatory and anti-catabolic properties in joint primary OA cells without any toxic effect. This data underpins naloxone & thalidomide repurpose to treat OA-associated inflammatory responses.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a significant threat to global health. This virus affects the respiratory tract and usually leads to pneumonia in most patients and acute respiratory distress syndrome (ARDS) in 15% of cases. ARDS is one of the leading causes of death in patients with COVID-19 and is mainly triggered by elevated levels of pro-inflammatory cytokines, referred to as cytokine storm. Interleukins, such as interleukin-6 (1L-6), interleukin-1 (IL-1), interleukin-17 (IL-17), and tumor necrosis factor-alpha (TNF-α) play a very significant role in lung damage in ARDS patients through the impairments of the respiratory epithelium. Cytokine storm is defined as acute overproduction and uncontrolled release of pro-inflammatory markers, both locally and systemically. The eradication of COVID-19 is currently practically impossible, and there is no specific treatment for critically ill patients with COVID-19; however, suppressing the inflammatory response may be a possible strategy. In light of this, we review the efficacy of specific inhibitors of IL6, IL1, IL-17, and TNF-α for treating COVID-19-related infections to manage COVID-19 and improve the survival rate for patients suffering from severe conditions. [ABSTRACT FROM AUTHOR]

Background: Treatment of locally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC) with photon radiation is the standard of care but shows only moderate success. Alterations in response toward DNA DSB repair, apoptosis, and senescence are underlying determinants of radioresistance in the tumor cells. Recently, senescence and the associated secretory phenotype (SASP) came into the focus of research and raised the need to identify the tumor-promoting molecular mechanisms of the SASP. The aim of this project was to unravel more of this process and to understand the impact of the IL1 pathway, which plays a major role in SASP. The studies were performed for photon and 12C-ion irradiation, which strongly vary in their effect on radioresistance. Materials and Methods: A panel of five HPV-negative HNSCC cell lines was treated with photon and 12C-ion irradiation and examined for clonogenic survival, DNA DSB repair, and senescence. SASP and IL1 gene expressions were determined by RNA sequencing and activation of the IL1 pathway by ELISA. A functional impact of IL1A and IL1B was examined by specific siRNA knockdown. Results: Cell killing and residual DSBs were higher after 12C-ion than after photon irradiation. 12C-ion induced more senescence with a significant correlation with cell survival. The impact on radioresistance appears to be less than after photon irradiation. The expression of SASP-related genes and the IL1 pathway are strongly induced by both types of irradiation and correlate with radioresistance and senescence, especially IL1A and IL1B which exhibit excellent associations. Surprisingly, knockdown of IL1A and IL1B revealed that the IL1 pathway is functionally not involved in radioresistance, DSB repair, or induction of senescence. Conclusions: IL1A and IL1B are excellent indicators of cellular radioresistance and senescence in HNSCC cells without functional involvement in these processes. Clearly more research is needed to understand the molecular mechanisms of senescence and SASP and its impact on radioresistance. [ABSTRACT FROM AUTHOR]

BackgroundTreatment of locally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC) with photon radiation is the standard of care but shows only moderate success. Alterations in response toward DNA DSB repair, apoptosis, and senescence are underlying determinants of radioresistance in the tumor cells. Recently, senescence and the associated secretory phenotype (SASP) came into the focus of research and raised the need to identify the tumor-promoting molecular mechanisms of the SASP. The aim of this project was to unravel more of this process and to understand the impact of the IL1 pathway, which plays a major role in SASP. The studies were performed for photon and 12C-ion irradiation, which strongly vary in their effect on radioresistance.Materials and MethodsA panel of five HPV-negative HNSCC cell lines was treated with photon and 12C-ion irradiation and examined for clonogenic survival, DNA DSB repair, and senescence. SASP and IL1 gene expressions were determined by RNA sequencing and activation of the IL1 pathway by ELISA. A functional impact of IL1A and IL1B was examined by specific siRNA knockdown.ResultsCell killing and residual DSBs were higher after 12C-ion than after photon irradiation. 12C-ion induced more senescence with a significant correlation with cell survival. The impact on radioresistance appears to be less than after photon irradiation. The expression of SASP-related genes and the IL1 pathway are strongly induced by both types of irradiation and correlate with radioresistance and senescence, especially IL1A and IL1B which exhibit excellent associations. Surprisingly, knockdown of IL1A and IL1B revealed that the IL1 pathway is functionally not involved in radioresistance, DSB repair, or induction of senescence.ConclusionsIL1A and IL1B are excellent indicators of cellular radioresistance and senescence in HNSCC cells without functional involvement in these processes. Clearly more research is needed to understand the molecular mechanisms of senescence and SASP and its impact on radioresistance.

Objective: There is a need to incorporate multiple tissues into in vitro OA models to evaluate novel therapeutics. This approach is limited by inherent donor variability. We present an optimized research tool: a human OA cartilage-synovium explant co-culture model (OA-EXM) that employs donor-matched lower and upper limit response controls combined with statistical approaches to address variability. Multiple rapid read-outs allow for evaluation of therapeutics while cataloguing cartilage-synovium interactions.Design: 48-h human explant cultures were sourced from OA knee arthroplasties. An OA-like cartilage-synovium co-culture baseline was established relative to donor-matched upper limit supraphysiological pro-inflammatory cytokine and lower limit OA cartilage or synovium alone controls. 100 nM dexamethasone treatment validated possible "rescue effects" within the OA-EXM dual tissue environment. Gene expression, proteoglycan loss, MMP activity, and soluble protein concentrations were analyzed using blocking and clustering methods.Results: The OA-EXM demonstrates the value of the co-culture approach as the addition of OA synovium increases OA cartilage proteoglycan loss and expression of MMP1, MMP3, MMP13, CXCL8, CCL2, IL6, and PTGS2, but not to the extent of supraphysiological stimulation. Conversely, OA cartilage does not affect gene expression or MMP activity of OA synovium. Dexamethasone shows dual treatment effects on synovium (pro-resolving macrophage upregulation, protease downregulation) and cartilage (pro-inflammatory, catabolic, and anabolic downregulation), and decreases soluble CCL2 levels in co-culture, thereby validating OA-EXM utility.Conclusions: The OA-EXM is representative of late-stage OA pathology, captures dual interactions between cartilage and synovium, and combined with statistical strategies provides a rapid, sensitive research tool for evaluating OA therapeutics. [ABSTRACT FROM AUTHOR]

There is crucial question on further therapeutic tactics for the management of such patients (within the severe epidemiological situation caused by the pandemic of new coronavirus SARS-CoV-2) due to widespread application of genetically engineered biologic drugs (GEBD)in management of immune mediated inflammatory diseases. This review sums up current data on the pathogenesis of COVID-19 with the development of acute respiratory distress syndrome associated with cytokine release syndrome (cytokine storm). The effects of GEBD on COVID-19 pathogenesis and their role in management of COVID-19 severe forms of are considered. This review presents the latest guidelines of international associations/consensus and observations of doctors of various specialties on the issue of interruption/continuation of GEBD therapy and with further consequence evaluation in case of interruption of biological therapy.

Osteoarthritis (OA) is hallmarked as a silent progressive rheumatic disease of the whole joint. The accumulation of inflammatory and catabolic factors such as IL6, TNFα, and COX2 drives the OA pathophysiology into cartilage degradation, synovia inflammation, and bone destruction. There is no clinical available OA treatment. Although traditional ayurvedic medicine has been using Boswellia serrata extracts (BSE) as an antirheumatic treatment for a millennium, none of the BSE components have been clinically approved. Recently, β boswellic acid (BBA) has been shown to reduce in vivo OA-cartilage loss through an unknown mechanism. We used computational pharmacology, proteomics, transcriptomics, and metabolomics to present solid evidence of BBA therapeutic properties in mouse and primary human OA joint cells. Specifically, BBA binds to the innate immune receptor Toll-like Receptor 4 (TLR4) complex and inhibits both TLR4 and Interleukin 1 Receptor (IL1R) signaling in OA chondrocytes, osteoblasts, and synoviocytes. Moreover, BBA inhibition of TLR4/IL1R downregulated reactive oxygen species (ROS) synthesis and MAPK p38/NFκB, NLRP3, IFNαβ, TNF, and ECM-related pathways. Altogether, we present a solid bulk of evidence that BBA blocks OA innate immune responses and could be transferred into the clinic as an alimentary supplement or as a therapeutic tool after clinical trial evaluations.

Mesenchymal stem cells (MSCs) belong to the tumour microenvironment and have been implicated in tumour progression. We found that the number of MSCs significantly increased in tumour-burdened mice driven by Fas-threshold signalling. Consequently, MSCs lacking Fas lost their ability to induce metastasis development in a pancreatic cancer model. Mixing of MSCs with pancreatic cancer cells led to sustained production of the pro-metastatic cytokines CCL2 and IL6 by the stem cells. The levels of these cytokines were dependent on the number of MSCs, linking Fas-mediated MSC-proliferation to their capacity to promote tumour progression. Furthermore, we discovered that CCL2 and IL6 were induced by pancreatic cancer cell-derived IL1. Importantly, analysis of patient transcriptomic data revealed that high FasL expression correlates with high levels of MSC markers as well as increased IL6 and CCL2 levels in pancreatic tumours. Moreover, both FasL and CCL2 are linked to elevated levels of markers specific for monocytes known to possess further pro-metastatic activities. These results confirm our experimental findings of a FasL-MSC-IL1-CCL2/IL6 axis in pancreatic cancer and highlights the role of MSCs in tumour progression. [ABSTRACT FROM AUTHOR]

Apoptosis-associated Speck-like protein containing a CARD (caspase activation and recruitment domain) (ASC), also called PYCARD/Target of Methylation-induced Silencing-1 (TMS1), was originally discovered as a protein that forms aggregates (“specks”) in human leukemia cells treated with chemotherapeutic agents. Its expression was found to be silenced by methylation in many human tumors, preventing tumor cells from undergoing apoptosis and supporting its role as a tumor suppressor. Subsequently, ASC was also identified as a central adaptor molecule of the inflammasome complex, which mediates the secretion of inflammatory cytokines (i.e., IL-1β and IL-18). Inflammatory cytokines have been shown to mediate tumor-promoting functions. Thus, in the context of cancer development and progression, ASC may exert opposing functions, i.e., be either tumor-suppressing by inducing tumor cell apoptosis, or tumor-promoting by favoring secretion of inflammatory cytokines (by tumor cells and/or tumor infiltrating myeloid cells) within the tumor microenvironment. Here, we report and discuss this dual role of ASC by also considering the final contribution of each of its two main functions in several cancer types, taking into consideration the correlation between ASC expression, clinical correlates, and patients’ survival. ASC and inflammasome targeting strategies are being developed. However, before the use of such treatments in clinical practice, it is fundamental to better dissect the role of ASC in different tumors, in order to privilege or avoid their use in those tumors in which ASC exerts an anti-tumor or pro-tumor function, respectively.

OBJECTIVE: To analyze the clinical efficacy of naloxone combined with acyclovir in the treatment of children viral encephalitis and the impacts on inflammatory factors IL1 and IL-6. PATIENTS AND METHODS: 96 children with viral encephalitis were retrospectively analyzed. They were treated from July 2013 to January 2014 in our hospital. They were divided into control group (45 cases treated with acyclovir) and observation group (51 cases treated with acyclovir combined with naloxone). Both groups were treated with comprehensive measures. Changes of the content of serum IL-1 and IL-6 in the two groups before and after treatment were monitored by enzyme-linked immunosorbent assay (ELISA). Signs, recovery time of clinical symptoms, total effective rate, occurrence of adverse reactions and adverse reactions after treatment of children in the two groups were compared. RESULTS: Levels of serum IL-1 and IL-6 of children in the control group and the observation group decreased after treatment, and the decrease was greater in the observation group (p<0.05). Signs and recovery time of clinical symptoms of the observation group were significantly shorter than that of the control group (p<0.05). Indexes of serum in the observation group were significantly lower than those of the control group after treatment (p<0.05). The total effective rate of the observation group was significantly higher than that of the control group (p<0.05). The prevalence of adverse reactions and sequelae in the observation group were lower than those in the control group (p<0.05). CONCLUSIONS: In the treatment of children, viral encephalitis has naloxone combined with ganciclovir had a more significant effect on the decrease of levels of serum IL-1 and IL-6; naloxone combined with acyclovir in the treatment of children viral encephalitis had better effects, lower adverse reactions and lower prevalence of sequelae compared with sole medication, which is worth clinical promotion. [ABSTRACT FROM AUTHOR]

Nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a cell-surface adhesion molecule that regulates cell migration and attachment. This study demonstrates the increase in Ninj1 protein expression during development of intestinal inflammation. Ninj1-deficient mice exhibited significantly attenuated bodyweight loss, shortening of colon length, intestinal inflammation, and lesser pathological lesions than wild-type mice. Although more severe inflammation and serious lesions are observed in wild-type mice than Ninj1-deficient mice, there were no changes in the numbers of infiltrating macrophages in the inflamed tissues obtained from WT and Ninj1-deficient mice. Ninj1 expression results in activation of macrophages, and these activated macrophages secrete more cytokines and chemokines than Ninj1-deficient macrophages. Moreover, mice with conditional deletion of Ninj1 in myeloid cells (Ninj1fl/fl; Lyz-Cre+) alleviated experimental colitis compared with wild-type mice. In summary, we propose that the Ninj1 in myeloid cells play a pivotal function in intestinal inflammatory conditions. [ABSTRACT FROM AUTHOR]

• Immune cells support islet β cells to finely tune insulin production. • Macrophage-derived IL-1β potentiates insulin secretion under steady state. • Type 2 immunity promotes insulin production in response to metabolic stress. • Further studies are needed to translate insulin secretion priming in the immunological context. Increasing evidence suggests a role for the immune system to finely tune metabolic homeostasis. The possibility that the immune system can likewise regulate islet endocrine function has only commenced drawing attention. Islet beta cells are the main producers of insulin and have to dynamically respond to fluctuating insulin demands of the body. While inflammation has long been considered as an important pathogenic feature of diabetes development, pioneer studies have shown that immune cells reside inside pancreatic islets under steady state and that components of the immune system can promote beta cell insulin production. The present review will thus highlight the recent research on specific immune pathways regulating beta cell function discussing the beneficial influence of innate immune cells. [ABSTRACT FROM AUTHOR]

Interleukin‐1 (IL1) is a cytokine that plays a role in inflammation and is a potential contributor to the inflammation present in tendinopathy. Its inhibition may be of use in the treatment of tendinopathy and has been a target for treatment. To evaluate how an IL1‐receptor antagonist (IL1‐RA) reverses pathologic changes associated with established patellar tendinopathy, we randomized 48 Sprague‐Dawley retired breeder rats into three groups having weekly bilateral patellar tendon injections for 6 weeks. The control group received 0.1 mL saline for 6 weeks. The intervention groups were treated with 0.1 mL 2% carrageenan for 4 weeks. Beginning at week three, the IL1‐RA group received 0.94 mg of the IL1‐RA (2.5 mg/kg) added to the 0.1 mL 2% carrageenan and 0.94 mg of the IL1‐RA alone for the final 2 weeks, while the CAR received 0.1 mL saline for the final 2 weeks. Animals were euthanized 6 weeks after initial injection. The CAR group demonstrated significantly (P < 0.05) shorter tendon lengths (7.81 ± 0.44 mm) than the control (8.25 ± 0.58 mm) and IL1‐RA (8.34 ± 0.52 mm) group (P < 0.05). Macroscopically, plaque‐like formations were reduced and margins of the tendon were more evident in the IL1‐RA group compared to the CAR group. CAR group demonstrated significantly greater histopathologic changes (inflammatory cell density, disorganization of collagen, nuclear rounding, and angiogenesis) than the control and IL1‐RA group. No significant difference in mechanical properties of the tendon was noted. These findings demonstrate IL1‐RA can reduce pathologic changes in the patellar tendon in an established tendonitis model although did not demonstrate a difference in mechanical properties. [ABSTRACT FROM AUTHOR]

Objective: Approximately 10%-20% of patients with familial Mediterranean fever (FMF) show an inadequate response to colchicine. In our cohort study, patients with FMF with or without amyloidosis and with an inadequate response to colchicine were treated with anakinra or canakinumab. Methods: Clinical and laboratory parameters, Mediterranean fever (MEFV) mutations, and patient-reported outcomes were analyzed in 31 patients treated with anakinra or canakinumab. Results: In a cohort of 250 adult patients with FMF, 31 patients were treated with anakinra (n=29) or canakinumab (n=2). The median Pras FMF severity score was 8 (range, 5-14) and correlated with the presence of high-penetrance MEFV mutations (p.Met-694-Val or p.Met-680-Ile). The FMF severity score was 11 in patients with two high-penetrance MEFV mutations (68%), 9 in those with a single high-penetrance MEFV mutation (19%), and 7.5 in those without high-penetrance MEFV mutations (13%, p=0.2). FMF-related amyloid A amyloidosis was diagnosed in 12 (39%) patients. Anakinra was used daily in 20 patients, thrice a week in 7, and upon demand during attacks in 2. Two patients were treated with canakinumab. IL-1-blocking treatment showed a rapid (2±3 days) and persistent suppression of FMF symptoms and inflammatory parameters. The frequency of FMF attacks was significantly reduced (p<0.003). Both patient- and physician-reported FMF activity significantly improved (p<0.0001). Conclusion: IL-1-blocking therapy was well tolerated over a median period of 2 years and reduced the frequency of FMF attacks in patients with colchicine-resistant FMF. [ABSTRACT FROM AUTHOR]

In preclinical models, IL-1β inhibition could enhance the efficacy of fluorouracil (5-FU). In this phase 2 study, we assessed the activity and safety of 5-FU plus bevacizumab and anakinra (an IL-1β and α inhibitor) in patients with metastatic colorectal (mCRC) refractory to chemotherapy and anti-angiogenic therapy. Eligible patients had unresectable mCRC; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were treated with a simplified acid folinic plus 5-FU regimen and bevacizumab (5 mg/kg) both administered by intravenous infusion for 30 min every 2 weeks. Anakinra (100 mg) was injected subcutaneously once daily. The primary endpoint was the 2-month response rate determined upon CHOI criteria. Thirty two patients with metastatic colorectal cancer were enrolled. Five patients demonstrated response (Choi criteria) and 22 patients had stable disease as the best 2-month overall response. Median progression-free and overall survival were 5.4 (95% CI, 3.6–6.6) and 14.5 months (95% CI, 9–20.6) respectively. Twenty patients experienced grade 3 toxicity. No grade 4 or 5 toxicity related to therapy occurred. The most common grade 3 adverse events were neutropenia in 8 (25%) patients, digestive side effects in 7 (21.9%) patients and hypertension in 6 (18.75%) patients. No treatment-related deaths or serious adverse events were reported.5-FU plus bevacizumab and anakinra has promising activity and a manageable safety profile, suggesting that this combination might become a potential treatment option for patients with refractory mCRC.

Overt infection by Propionibacterium acnes is lacking in many SAPHO syndromes, and antibiotics have only a transient and incomplete effect, either in SAPHO syndrome or acne. As several auto-inflammatory bone disorders sharing overproduction of IL-1β can mimic SAPHO, this syndrome could partly depend on genetically encoded overproduction of IL-1β. However, cyclic intracellular infections, mostly by P. acnes, can contribute to the enhanced IL-1β release by some skin cells, and probably by bone cells. P. acnes is indeed a powerful trigger of NLRP3-inflammasome activation and IL-1β, leading to osteitis and enhanced mesenchymal cells differentiation in osteoblasts. Recent advances in the understanding of acne suggest that first steps of this disorder are not driven by P. acnes, but by a relative deficiency of FoxO1 within the nucleus of sebaceous cells. A similar defect of FoXO1 in bone cells should also be sought in SAPHO, since repression of FoxO1 gene is found in lesional psoriasis skin, and is associated with an increased number of osteoblasts and high bone mass in mice. FoxO1 selectively promotes IL-1β production, so that its downregulation could help some P. acnes t escape innate immunity and persist in a latent state in bone cells, including mesenchymal stem cells. However, P. acnes itself possibly contributes to FoxO1 downregulation, like H. pylori infection which induces nuclear inactivation of FoxO1 in human gastric cells to slow down autophagic clearance. As bisphosphonates, which often improve SAPHO syndromes, enhance autophagy, it may be worth testing whether their combination with antibiotics is synergistic in SAPHO syndromes. [ABSTRACT FROM AUTHOR]

As a cellular degradation mechanism, autophagy exerts crucial and complicated effects on HCC development. Liver non-parenchymal cells, including hepatic resident macrophage Kupffer cells, also play important roles in this process. However, most associated studies have focused on the influence of the autophagy level in hepatic cells and HCC cells, but not liver non-parenchymal cells. Based on our previous study, we confirmed that Atg5 silence in the liver during the preneoplastic stage facilitated liver fibrosis, inflammation and, ultimately, tumorigenesis. We further found that autophagy deficiency promotes the production of inflammatory and fibrogenic factors in macrophages. Moreover, Kupffer cell depletion rescued the tumor-promoting effect of autophagy deficiency during the preneoplastic stage. In autophagy-deficient macrophages, mitochondrial ROS mediated inflammation- and fibrosis-promoting effects by increasing IL1α/β production via enhancing NF-κB-associated pathways. Both blocking of mitochondrial ROS and blocking the IL1 receptor stopped the promotion of fibrosis, inflammation and tumorigenesis resulting from Atg5 knockdown during the preneoplastic stage. In conclusion, autophagy-deficient Kupffer cells promote liver fibrosis, inflammation and, finally, hepatocarcinogenesis during the preneoplastic stage by enhancing mitochondrial ROS- NF-κB-IL1α/β pathways. [ABSTRACT FROM AUTHOR]

Some viruses such as SARS, SARS-CoV-2, and MERS cause an imbalance in immune responses and leads to an acute inflammatory reaction named cytokine storm. In this situation, an anti-inflammatory component can modulate the immune system and decrease mortality. The aim of this study was investigate the potential of leukoreduction filters (LRFs) in creating an anti-inflammatory compound. In this experimental study, firstly optimal dose of the anti-inflammatory drug was obtained through LRFs treatment with 0.1 mg, 0.4 mg, 0.6 mg of Betamethasone. Then inflammatory and anti-inflammatory cytokine in gene and protein level was evaluated. In the next step, LRFs were categorized into treatment 1, treatment 2, control assay, and control groups and treated with the optimal dose of the drug. Finally, the obtained compound was investigated for the concentration of IL1, IL6, and TNF-α as inflammatory and IL4, IL1Ra, and IL10 as anti-inflammatory cytokines. The results of the current study showed that the concentration of 0.4 mg of Betamethasone lead to a significant increase of anti-inflammatory cytokine in gene and protein levels. The results also showed that the Betamethasone treated groups (treatment1) causes a significant increase in the secretion of anti-inflammatory cytokine compares to the control while inflammatory cytokine remained at the control level. The results showed that under influence of anti-inflammatory drug treatments the production and secretion of anti-inflammatory cytokines can be induced in LRFs. [ABSTRACT FROM AUTHOR]

Background: The improvement of colitis symptoms by treatment with IL-12/23 p40 neutralizing antibody should increase the muscle mass and the function of the sarcopenia phenotype., Methods: An experimental colitis model was induced by oral administration of 2% dextran sulfate sodium (DSS) for 7 days. During induction of colitis, IL-12/23 p40 neutralizing antibody was injected twice on Days 3 and 5. The total body mass index was measured by dual-energy X-ray absorptiometry. The muscle function was measured by forelimb grip strength and fatigue running distance. The muscle fibre cross-sectional area (CSA) was calculated after the transverse section and haematoxylin and eosin staining, and gene expression was confirmed by RT-qPCR. Differentiated C2C12 cells were used as in vitro models and treated with recombinant IL12/23 proteins to mimic the enhanced cytokines in colitis., Results: The symptoms of colitis were alleviated by injection of IL-12/23 p40 neutralizing antibody compared with phosphate-buffered saline (PBS), and the disease activity index score was significantly lower on Day 8 (0.0 ± 0.00 of cont. vs. 11.3 ± 0.9 of DSS + PBS, P < 0.0001; DSS + PBS vs. 7.7 ± 1.25 of DSS + p40Ab, P < 0.0001). The CSA of the gastrocnemius and tibialis anterior muscle fibres decreased in mice with DSS-induced colitis (gastrocnemius, 1258.2 μm 2 ± 176.45 of cont. vs. 640.1 μm 2 ± 59.83 of DSS + PBS, P < 0.0001; tibialis anterior, 1251.8 μm 2 ± 331.48 of cont. vs. 678.9 μm 2 ± 67.59 of DSS + PBS, P < 0.0001), and the treatment of IL-12/23 p40 neutralizing antibody partially restored CSA of the gastrocnemius (640.1 μm 2 ± 59.83 of DSS + PBS vs. 1062.0 μm 2 ± 83.41 of DSS + p40Ab, P < 0.0001) and tibialis anterior (678.9 μm 2 ± 67.59 of DSS + PBS vs. 1105.3 μm 2 ± 143.15 of DSS + p40Ab, P = 0.0003).vs. 640.1 μm 2  ± 59.83 of DSS + PBS, P < 0.0001) and tibialis anterior (1251.8 μm 2  ± 331.48 of cont. vs. 678.9 μm 2  ± 67.59 of DSS + PBS, P < 0.0001), and the treatment of IL-12/23 p40 neutralizing antibody partially restored CSA of the gastrocnemius (640.1 μm 2  ± 59.83 of DSS + PBS vs. 1062.0 μm 2  ± 83.41 of DSS + p40Ab, P < 0.0001) and tibialis anterior (678.9 μm 2  ± 67.59 of DSS + PBS vs. 1105.3 μm 2  ± 143.15 of DSS + p40Ab, P = 0.0003). In the evaluation of muscle function, grip strength and fatigue distance decreased by colitis were partially restored (grip strength: 139.9 g ± 5.38 of cont. vs. 83.9 g ± 5.48 of DSS + PBS, P < 0.0001; DSS + PBS vs. 118.6 g ± 4.05 of DSS + p40Ab, P < 0.0001; fatigue distance: 872.5 m ± 104.01 of cont. vs. 58.2 m ± 107.72 of DSS + PBS, P < 0.0001; DSS + PBS vs. 328.0 m ± 109.71 of DSS + p40Ab, P = 0.0015) by injection of IL-12/23 p40 neutralizing antibody., Conclusions: Our study demonstrates that Il-12/23 acts directly on muscle to induce atrophy, and the IL-12/23 p40 neutralizing antibody is effective not only in suppressing colitis but also in maintaining muscle mass and improving muscle function in an experimental colitis model., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Humans are exposed to chemicals and PM (particulate matter), including ultrafine particles (nanoparticles), mainly through inhalation. This creates a risk to their health. Another effect to exposure is expression of cytokines and their role in lung inflammation and morphpathogenesis. We conducted a pilot project based on testing of realistic exposure scenarios by describing morphological changes of the respiratory tract in Wistar rats (male) during a 30-day exposure in office where there was high intensity of printing activities. Tracheal tissue of experimental animals had increasing concentrations of inflammatory interleukin IL-1 and decreasing concentrations of IL-6 and TNF-α. The lungs of the experimental animals tended to show focal infiltration of inflammatory cells, vascular plethora, focal and/or diffuse localisation of lymphatic nodules, and also vascular sclerosis and focal emphysema. The results suggested potential dangerous and adverse effect of poor indoor air quality (particles, including nanoparticles, and chemical compounds) on respiratory tract tissue of rats. [ABSTRACT FROM AUTHOR]

ABSTRACT This study evaluated if inhibiting IL1-β activity with an IL1-receptor antagonist (IL1-RA) will prevent pathologic changes commonly seen in tendinopathy. Thirty-six Sprague-Dawley retired-breeder rats were divided into three groups having weekly bilateral patellar tendon injections: CON (0.1 ml Saline), CAR (0.1 ml 2% carrageenan), IL1-RA (0.1 ml 2% CAR plus 0.94 mg of the IL1-RA, 2.5 mg/kg). Carrageenan was used to establish tendinopathy in two groups due to its ability to develop tendinopathy in prior studies. Animals were euthanized 3 weeks after initial injection. The CAR group demonstrated significantly ( p < 0.05) shorter tendon lengths (8.61 ± 0.38 mm) relative to CON (8.94 ± 0.38 mm) that was prevented in the IL1-RA (9.02 ± 0.30 mm) as well as significantly increased collagenase activity in the CAR (0.061 ± 0.043) compared to CON (0.027 ± 0.015) ( p< 0.05). By histological evaluation, the CAR group demonstrated significantly greater inflammation than IL1-RA, and CON ( p < 0.05). CAR showed a trend for increased cross-sectional area relative to CON that was absent in the IL1-RA. IL1-RA can effectively inhibit the development of mechanical, chemical, and histologic changes seen with carrageenan-induced tendonitis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:616-622, 2016. [ABSTRACT FROM AUTHOR]

Abstract Approximately 10% of gastric cancer cases show familial clustering but only 1-3% of gastric carcinomas arise as a result of inherited gastric cancer predisposition syndromes. Direct proof that Hereditary Gastric Cancer a genetic disease with a germline gene defect has come from the demonstration of co-segregation of germline E-cadherin (CDH1) mutations with early onset diffuse gastric cancer in families with an autosomal dominant pattern of inheritance (HDGC). E-cadherin is a transmembrane calcium-dependent cell-adhesion molecule involved in cell-junction formation and the maintenance of epithelial integrity. In this review, we describe frequency and type of CDH1 mutations in sporadic and familial gastric cancer. Further we demonstrate the functional significance of some CDH1 germline missense mutations found in HDGC. We also discuss the CDH1 polymorphisms that have been associated to gastric cancer. We report other types of malignancies associated to HDGC, besides diffuse gastric cancer. Moreover, we review the data available on putative alternative candidate genes screened in familial gastric cancer. Finally, we briefly discuss the role of low-penetrance genes and Helicobacter pylori in gastric cancer. This knowledge is a fundamental step towards accurate genetic counselling, in which a highly specialised pre-symptomatic therapeutic intervention should be offered.

Osteoarthritis (OA) affects more than 300 million people worldwide and it is about to become the first disabling disease. OA is characterized by the progressive degradation of the articular cartilage but is a disease of the whole joint. Articular innate immune responses (IIR) associated with tissue degradation contribute to its progression. However, no treatment is available to block these IIRs. Through data text mining and computational pharmacology, we identified two clinical available drugs, naloxone, and thalidomide, with potential inhibitory properties on toll-like receptor 4 (TLR4), a major activator of these IIR. Proteome analysis confirmed that activation of this receptor or the IL1 receptor generated OA-like and gout-like proteomic changes in human primary chondrocytes. Both compounds were found to block TLR4 complex and inhibit TLR4 and IL1R-mediated IIR in OA chondrocytes, osteoblasts, and synoviocytes. Furthermore, naloxone and thalidomide inhibitory effects involved the downregulation of the NLRP3 inflammasome pathway, which is downstream of TLR4/IL1R signaling. We demonstrated that these compounds, within a therapeutic range of concentrations, exhibited anti-inflammatory and anti-catabolic properties in joint primary OA cells without any toxic effect. This data underpins naloxone & thalidomide repurpose to treat OA-associated inflammatory responses. [Display omitted] • TLR4 /IL1R activation induces OA- & gout-like proteomic changes in OA chondrocytes. • Naloxone & thalidomide have higher binding affinity to TLR4 than TLR4 agonist LPS. • Naloxone & thalidomide inhibit TLR4 /IL1R-mediated responses in OA joint cells. • Naloxone & thalidomide downregulate the NLRP3 inflammasome pathway. • Naloxone & thalidomide repurposing is a potential new therapeutic tool to treat OA. [ABSTRACT FROM AUTHOR]

Interleukin 1 and its receptors are associated with allergic diseases such as asthma. In the present study, we measured DNA methylation at the IL1R1 and IL1R2 gene loci and assessed for associations with asthma-related phenotypes and gene expressions. We found that asthmatic and atopic individuals have higher IL1R2 promoter DNA methylation than control subjects. Additionally, we observed a negative correlation between DNA methylation at the IL1R2 promoter and IL1R2 mRNA expression. These results suggest for the first time that IL1R2 promoter DNA methylation is associated with its gene repression in allergic diseases such as asthma. [ABSTRACT FROM AUTHOR]

Chronic cavitary pulmonary aspergillosis ( CCPA) is a progressive lung condition with a 10-30% annual mortality. Although overtly immunocompetent, some immunogenetic defect in patients is likely. To investigate a possible immunogenetic defect in CCPA, we analysed biologically plausible candidate genes in 112 CCPA patients and 279 healthy controls in a genetic association study of genes involved in the post-recognition immune response to Aspergillus fumigatus. We also compared gene expression in monocyte-derived macrophages from subjects with and without disease, both at baseline and during stimulation with A. fumigatus. Compared with macrophages from healthy subjects, CCPA macrophages showed unrestrained rises in IL1A, IL1B, IL6, IRAK2 and TRAF6 throughout the experiment, and a lack of expression of TGFB1 at 9 h. Single nucleotide polymorphisms (SNPs) associated with CCPA were found in IL1B ( n = 2), IL1 RN and IL15 ( n = 3). Uncontrolled expression of IL1 and IL6 and continuing high levels of these cytokines may result in continuing cellular influx and pro-inflammatory responses, inhibiting disease resolution and contributing to disease progression in CCPA. The association of SNPs in IL1B, IL1 RN and IL15 with CCPA supports a role for the IL1 pathway, as well as implicating the IL15 gene, in susceptibility to CCPA. [ABSTRACT FROM AUTHOR]

Background A deficiency in the counter-regulatory mechanisms of interleukin 1 (IL1) may play a significant role in endometriosis pathogenesis and associated chronic inflammation. The aim of this study was to investigate peripheral blood levels of soluble IL1 receptor accessory protein (sIL1RAP), a potent natural inhibitor of IL1, in women with and without endometriosis. Methods Peripheral blood samples were collected from women with endometriosis (n = 47) consulting for infertility, pelvic pain or tubal ligation, in whom the disease was diagnosed at laparoscopy. Control healthy women (n = 27) were requesting tubal ligation or reanastomosis and had no visible evidence of endometriosis at laparoscopy. sIL1RAP levels were determined by ELISA, whereas estradiol (E2) and progesterone (P4) levels were determined by competitive immunoassays. Results sIL1RAP levels were significantly decreased in women with early endometriosis stages compared to controls (p < 0.05) and markedly during the proliferative phase of the menstrual cycle (p < 0.001). Actually, while sIL1RAP were significantly increased in the proliferative compared to the secretory phase in normal women (p < 0.0001) and peaked at the end of this phase, sIL1RAP remained consistently low and showed non-significant variations throughout the menstrual cycle in women with endometriosis. Conclusions Lower circulating levels of sIL1RAP points to a significant impairment in the counterregulatory mechanisms of IL1, which in view of the cytokine's potent inflammatory and growth-promoting properties may play a significant role in the pathophysiology of endometriosis. [ABSTRACT FROM AUTHOR]

Background and Aim Gastric ulcer healing is a complex process involving cell proliferation and tissue remodeling. Sonic hedgehog ( Shh) activates the Shh signaling pathway, which plays a key role in processes such as tissue repair. Shh and interleukin 1β ( IL1β) have been reported to influence the proliferation of gastric mucosa. We evaluated the relationships between the speed of gastric ulcer healing and the levels of expression of Shh and IL1β. Methods The study included 45 patients (mean age 71.9 ± 9.0 years; M/ F, 30/15) who underwent endoscopic submucosal dissection ( ESD) for gastric cancer, followed by standard dose of oral proton-pump inhibitor for 4 weeks. Subsequently, the size of ESD-induced artificial ulcers were measured to determine the speed of gastric ulcer healing, and regenerating mucosa around the ulcers and appropriately matched controls were collected from patients by endoscopic biopsy. Polymerase chain reaction (PCR) array analysis of genes in the Shh signaling pathway was performed, and quantitative reverse transcription (RT)-PCR was used to measure IL1β mRNA. Results The levels of Shh and IL1β mRNA were 3.0 ± 2.7-fold and 2.5 ± 2.5-fold higher, respectively, in regenerating mucosa of artificial ulcers than in appropriately matched controls, with the two being positively correlated (r = 0.9, P < 0.001). Shh (r = 0.8, P < 0.001) and IL1β (r = 0.7, P < 0.005) expression was each positively correlated with the speed of gastric ulcer healing, but multivariate analysis showed that Shh expression was the only significant parameter ( P = 0.045). Conclusions Expression of Shh was correlated with the speed of gastric ulcer healing, promoting the regeneration of gastric mucosa. [ABSTRACT FROM AUTHOR]

Objective: Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi's sarcoma (KS) and Primary effusion lymphoma (PEL), which are usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin1 (IL1) family is a major mediator for inflammation response and has functional role in both innate and adaptive immunity. In contrast to the well-studied IL1 molecules, the activation and functional role of IL1 receptor/co-receptor and other related ligands, such as the IL1 receptor accessory protein (IL1RAP), in KSHV pathogenesis and tumorigenesis remain almost unknown., Methods: In the current study, a series of KSHV negative and positive primary or tumor cells, as well as AIDS-KS tumor samples from cohort HIV+ patients were used to compare and determine the activation status of IL1 signaling molecules, and their functional roles in KSHV pathogenesis., Results: We reported the high activation of multiple IL1 signaling molecules, including IL1, IL36, IL1R1, IL1RAP and IRAKs, during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV-related malignancies. Directly targeting these molecules especially IL1R1 and IL1RAP significantly impaired the survival and growth of KSHV+ tumor cells, as well as their colony formation on 3-D culture., Conclusion: Our data indicate the importance of IL1 signaling molecules in KSHV pathogenesis and tumorigenesis, which may represent attractive therapeutic targets against these virus-associated diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Song, James, Plaisance-Bonstaff, Post, Qin and Dai.)

Abstract: Many epidemiological studies have investigated IL1α and IL1β polymorphisms with SLE risk, but no conclusions are available because of conflicting results. This meta-analysis was performed to more precisely estimate the relationships. The databases of PubMed updated to September 1st, 2012 were retrieved. Odds ratio (OR) and corresponding 95% confidence interval (95% CI) as effect size were calculated by a fixed- or random-effect model. In total, six case–control studies for IL1β−511C/T, four studies for IL1β+3953C/T, three studies for IL1α−889C/T and three studies for IL1α+4845G/T were involved in this analysis. The results indicated that for IL1α−889C/T polymorphism T allele was associated with decreased risk of SLE (OR (95% CI)) (T vs. C: 0.802 (0.679–0.949); TT+CT vs. CC: 0.615 (0.380–0.995); TT vs. CC: 0.679 (0.466–0.989)). However, when analysis for TT vs. CT+CC was conducted, the result indicated that IL1α−889C/T polymorphism was not associated with SLE (OR (95% CI): 0.847 (0.595–1.205)). Combined analysis indicated that IL1β−511C/T polymorphism was not overall associated with risk of SLE (OR (95% CI)) (T vs. C: 1.113 (0.954–1.298); TT vs. CT+CC: 1.146 (0.889–1.447); TT+CT vs. CC: 1.145 (0.903–1.452); TT vs. CC: 1.255 (0.928–1.698)). When subgroup analysis for Asian ethnicity was conducted, the results indicated that IL1β−511C/T polymorphism was associated with SLE only for TT vs. CT+CC (OR (95% CI): 1.468 (1.001–2.152)), but was not associated for T vs. C (OR (95% CI): 1.214 (0.955–1.544)), TT+CT vs. CC (OR (95% CI): 1.112 (0.765–1.615)) and TT vs.CC (OR (95% CI): 1.411 (0.896–2.222)). In addition, overall analyses indicated that IL1β+3953C/T and IL1α+4845G/C polymorphisms were also not associated with risk of SLE (OR (95% CI)) (for IL1β+3953C/T T vs. C: 0.996 (0.610–1.626), TT vs. CT+CC: 0.658 (0.318–1.358), TT+CT vs. CC: 1.021 (0.618–1.687), TT vs. CC: 0.640 (0.309–1.325); for IL1α+4845G/T T vs. G: 1.067 (0.791–1.440), TT+GT vs. GG: 0.934 (0.646–1.351)).This study inferred that IL1α−889C/T polymorphism might be moderately associated with SLE, but no sufficient evidence was available to support any associations between IL1β+3953C/T or IL1α+4845G/C polymorphisms and SLE. We could not draw a definite conclusion between IL1β−511C/T polymorphism and risk of SLE owing to the limited data. Further large sample-sized studies should be required. [Copyright &y& Elsevier]

OBJECTIVE: External apical root resorption (EARR) is permanent shortening of the end of the tooth root. It is a common clinical complication of orthodontic treatment. Polymorphisms in the interleukin I (ILI) gene cluster have been related to an increased EARR risk. The aim of this study was to analyze possible associations of ILI gene variants with EARR in Czech population. SUBJECTS AND METHODS: In this case-control study, 32 patients with EARR (age 15.0 ± 4.1 years) and 74 controls (age 15.2 ± 5.3 years) were genotyped using PCR-based methods for ILIA (-889C/T), ILIB (+3953C/T), and ILIRN [ILI receptor antagonist, variable number tandem repeat (VNTR)] gene polymorphisms. RESULTS: While no statistical significant differences in the ILIA and ILIB genotype, allele and reconstructed ILI haplotype frequencies between patients with EARR and controls were found, marginally significant differences were observed in the frequencies of ILIRN variant (P = 0.05 for *22 genotype and P = 0.06 for a short (2) allele). In addition, significant associations between ILIRN*I2, *22 genotypes and the short (2) allele and EARR were identified in the subgroup of girls (P = 0.04 and P = 0.02, P = 0.02). CONCLUSIONS: Although no significant role of ILIA (-889C/T) and ILIB (+3953C/T) variants in EARR was confirmed, ILIRN VNTR may be associated with EARR, especially in girls. [ABSTRACT FROM AUTHOR]

Abstract: The microbiota of Westerners is significantly reduced in comparison to rural individuals living a similar lifestyle to our Paleolithic forefathers but also to that of other free-living primates such as the chimpanzee. The great majority of ingredients in the industrially produced foods consumed in the West are absorbed in the upper part of small intestine and thus of limited benefit to the microbiota. Lack of proper nutrition for microbiota is a major factor under-pinning dysfunctional microbiota, dysbiosis, chronically elevated inflammation, and the production and leakage of endotoxins through the various tissue barriers. Furthermore, the over-comsumption of insulinogenic foods and proteotoxins, such as advanced glycation and lipoxidation molecules, gluten and zein, and a reduced intake of fruit and vegetables, are key factors behind the commonly observed elevated inflammation and the endemic of obesity and chronic diseases, factors which are also likely to be detrimental to microbiota. As a consequence of this lifestyle and the associated eating habits, most barriers, including the gut, the airways, the skin, the oral cavity, the vagina, the placenta, the blood–brain barrier, etc., are increasingly permeable. Attempts to recondition these barriers through the use of so called ‘probiotics’, normally applied to the gut, are rarely successful, and sometimes fail, as they are usually applied as adjunctive treatments, e.g. in parallel with heavy pharmaceutical treatment, not rarely consisting in antibiotics and chemotherapy. It is increasingly observed that the majority of pharmaceutical drugs, even those believed to have minimal adverse effects, such as proton pump inhibitors and anti-hypertensives, in fact adversely affect immune development and functions and are most likely also deleterious to microbiota. Equally, it appears that probiotic treatment is not compatible with pharmacological treatments. Eco-biological treatments, with plant-derived substances, or phytochemicals, e.g. curcumin and resveratrol, and pre-, pro- and syn-biotics offers similar effects as use of biologicals, although milder but also free from adverse effects. Such treatments should be tried as alternative therapies; mainly, to begin with, for disease prevention but also in early cases of chronic diseases. Pharmaceutical treatment has, thus far, failed to inhibit the tsunami of endemic diseases spreading around the world, and no new tools are in sight. Dramatic alterations, in direction of a paleolithic-like lifestyle and food habits, seem to be the only alternatives with the potential to control the present escalating crisis. The present review focuses on human studies, especially those of clinical relevance. [Copyright &y& Elsevier]

Osteoarthritis (OA) is a frequent, destructive joint disease, with debilitating impact on a society regarding medical, social, and economic issues. Although causes of primary OA were still not fully elucidated, evidence points to complex genetic risk that varies among different population groups, including the interleukin-1 (IL-1) gene cluster. Here, we sought to determine allelic and genotypic frequencies of the IL-1β (IL1B) and the IL-1 receptor antagonist (IL1RN) genes using single nucleotide polymorphism (SNP) at -511(G>A; rs16944) and the variable number tandem repeat (VNTR) in a case-control study with 238 patients that have undergone total or partial knee replacement and 495 healthy blood donors as controls in Croatia. The alleles of the IL1B gene at -511G>A were detected by Taqman real-time polymerase chain reaction (PCR) method and IL1RN VNTR by amplifying its DNA by PCR. The genotypes 1-2/1-2 and 2-1/2-2 at IL1B G -511A-IL1RN (VNTR) showed trends for association with the occurrence of the knee OA in this population ( P = 0.09; P = 0.07, respectively). Furthermore, neither the alleles nor the haplotypes were found associated with the predisposition to knee OA. Our findings suggest that knee OA might have a different genetic risk in this Caucasian population. We did not found significant association of the IL1 gene cluster (IL1B-IL1RN) with severe knee OA. However, we found that two genotypes (1-2/1-2 and 2-1/2-2) show a trend toward association with susceptibility to disease. [ABSTRACT FROM AUTHOR]

Abstract: Interleukin 1 (IL1) may play an important role in endometriosis-associated pelvic inflammation, and natural specific inhibitors, including soluble IL1 receptor accessory protein (sIL1RAcP) and soluble IL1 receptor type 2 (sIL1R2), are critical for counterbalancing the pleiotropic effects of IL1. The objective of this study was to evaluate the levels of sIL1RAcP, together with those of sIL1R2 and IL1β, in the peritoneal fluid of women with and without endometriosis. Peritoneal fluid samples were obtained at laparoscopy and assessed by ELISA. sIL1RAcP concentrations were reduced in endometriosis stages I–II and III-IV. sIL1R2 concentrations were decreased, and those of IL1β were significantly increased in endometriosis stages I–II. sIL1RAcP and sIL1R2 concentrations were significantly decreased in the secretory phase of the menstrual cycle, and IL1β concentrations were elevated in the proliferative and the secretory phases. sIL1RAcP and sIL1R2 concentrations were reduced in women with endometriosis who were infertile, fertile, suffering from pelvic pain or pain-free. However, IL1β concentrations were significantly reduced in women with endometriosis who were infertile or had pelvic pain. These changes may exacerbate the local peritoneal inflammatory reaction observed in women with endometriosis and contribute to endometriosis pathophysiology and the major symptoms of this disease. [Copyright &y& Elsevier]

Several genes that modify risk of factor VIII (FVIII) inhibitors in haemophilia A patients have been identified. Aside from the underlying mutations that cause haemophilia A, inhibitor risk appears to be modified by polymorphisms in various cytokines and immunomodulators including IL10, TNFα and CTLA4. HLA haplotypes have not been strong determinants of inhibitor risk. We sought to confirm previous observations on FVIII inhibitor risk-modifying genes and to test new candidate genes encoding various otherTH1/TH2 cytokines. We also sought to determine whether normal FVIII gene polymorphisms affect inhibitor risk in caucasians. We studied 915 caucasian, severe haemophilia A patients (282 inhibitor cases and 633 non-inhibitor controls). Genes were analysed using 368 tagging single nucleotide polymorphisms starting 20 kb 5′ and ending 10 kb 3′ of each gene's coding sequence; four other polymorphisms (factor V Leiden & prothrombin 20210 polymorphisms and two in HFE) were also evaluated. Haplotypes that increased inhibitor risk were found in IL10 (OR = 1.33, P = 0.04), IL12 (OR = 1.31, P = 0.04) and IL1α (OR = 2.16, P = 0.034). Protective haplotypes were seen in IL2 (OR = 0.69, P = 0.008) and IL1β (OR = 0.75, P = 0.02). One rare haplotype in the FVIII gene increased the risk of inhibitor development by nearly fourfold (OR = 3.8, P = 0.004). We replicate previous findings for IL10; identify new associations with IL1, IL2 and IL12; and identify a rare FVIII haplotype in caucasians that is associated with increased inhibitor risk. [ABSTRACT FROM AUTHOR]

Abstract: It has been shown that coal dust exposure stimulates inflammatory response leading to increased release of cytokines from monocytes such as TNF-alpha and IL1. These released cytokines play the key role in the pathogenesis of pneumoconiosis including coal workers’ pneumoconiosis. In this study, we investigated TNFA, IL1A, IL1B and IL1RA genes variations on basal, lipopolysaccharide and coal dust-induced cytokine release from blood monocytes of homozygous allele and minor variant allele carriers in Turkish coal workers and CWP patients. According to the genotyping results, TNFA –238 gene polymorphism was found as a risk factor in CWP development (OR=3.79) and to in vitro results; release of both TNF-alpha and IL1 cytokines from the monocytes in CWP patients was significantly increased compared to the healthy workers. Also, LPS and coal dust stimulated release of TNF-alpha, which was significantly higher in allele 2 carriers compared to subjects carrying allele 1 in both the groups. These data suggest that the coal dust-induced release of TNF-alpha from monocytes may be a useful biomarker of CWP. [Copyright &y& Elsevier]

BACKGROUND: Interleukin 1 (IL1) plays an important role in the physiology of human endometrium and is recognized as a major and early embryonic signal. Tight control over the local endometrial action of this cytokine is critical for normal reproductive functions. The coordinated regulation of IL1 receptors types I and II (IL1R1 and IL1R2) and IL1 receptor antagonist (IL1RA) in endometrial cells may represent one of the principle mechanisms involved in the control of IL1 local effects. The objective of this study was to investigate the regulation of IL1Rs in human endometrial epithelial cells in response to IL1. [ABSTRACT FROM PUBLISHER]

Brain glial cells, five times more prevalent than neurons, have recently received attention for their potential involvement in epileptic seizures. Microglia and astrocytes, associated with inflammatory innate immune responses, are responsible for surveillance of brain damage that frequently results in seizures. Thus, an intriguing suggestion has been put forward that seizures may be facilitated and perhaps triggered by brain immune responses. Indeed, recent evidence strongly implicates innate immune responses in lowering seizure threshold in experimental models of epilepsy, yet, there is no proof that they can play an independent role in initiating seizures in vivo. Here, we show that cortical innate immune responses alone produce profound increases of brain excitability resulting in focal seizures. We found that cortical application of lipopolysaccharide, binding to toll-like receptor 4 (TLR4), triples evoked field potential amplitudes and produces focal epileptiform discharges. These effects are prevented by pre-application of interleukin-1 receptor antagonist. Our results demonstrate how the innate immune response may participate in acute seizures, increasing neuronal excitability through interleukin-1 release in response to TLR4 detection of the danger signals associated with infections of the central nervous system and with brain injury. These results suggest an important role of innate immunity in epileptogenesis and focus on glial inhibition, through pharmacological blockade of TLR4 and the pro-inflammatory mediators released by activated glia, in the study and treatment of seizure disorders in humans. [ABSTRACT FROM PUBLISHER]

Abstract: Background and purpose: Recent findings implicating specific gene polymorphisms of the interleukin-1 superfamily gene cluster in the risk of developing athero-thrombotic disorders have generated great interest. However, to date, no prospective, genetic–epidemiological data are available. Methods: Using DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we evaluated seven gene polymorphisms within the interleukin-1 gene cluster among 599 individuals who subsequently developed athero-thrombotic event and among 599 age- and smoking-matched individuals who remained free of reported cardiovascular disease during follow-up (341 incident myocardial infarction matched case-control pairs and 258 incident ischemic stroke matched case-control pairs). Results: Overall, we observed little evidence of association between the polymorphisms tested and risk of incident athero-thrombotic events. Further adjustment for traditional cardiovascular risk factors yielded similar null findings. Of note, a modest association of rs1143623 with reduced risk of incident MI was found (recessive model: OR=0.455, 95% CI=0.215–0.960, uncorrected p =0.039). However, this finding was not corrected for multiple testing, and thus requires cautious interpretation. Conclusion: In contrast to prior retrospective studies, our prospective data suggest that the IL-1 cluster gene variation is not associated with risk of athero-thrombotic disorders. [Copyright &y& Elsevier]

Objective: To evaluate the levels of interleukin-1β (IL1β) and its inhibitory soluble interleukin-1 receptor type II (IL1R2) in the peritoneal fluid (PF) of normal women and patients with endometriosis suffering from pelvic pain and infertility. Design: Retrospective study using ELISA to measure peritoneal fluid IL1β and soluble IL1R2. Setting: Gynecology clinic and human reproduction research laboratory. Patient(s): Sixty-eight normal women and 154 women with endometriosis. Intervention(s): Peritoneal fluid samples were obtained at laparoscopy. Main Outcome Measure(s): IL1β and soluble IL1R2 concentrations in the PF samples. Result(s): This study showed a marked decrease in peritoneal soluble IL1R2 levels in women with endometriosis compared to normal women and a concomitant increase in the levels of IL1β. Both fertile and infertile women with endometriosis had lower soluble IL1R2 and higher IL1β concentrations than fertile women having a normal gynecological status, but the difference was more significant in infertile endometriosis patients. Compared with normal controls, the decrease in soluble IL1R2 levels was less significant in women with endometriosis than without pelvic pain, whereas the increase in IL1β concentrations was statistically significant only in women with endometriosis reporting pelvic pain. Conclusion(s): This study revealed an imbalance between IL1β and its decoy inhibitory receptor type 2 in women with endometriosis, which was particularly obvious in those who were infertile, and suggests that a defect in the local control of IL1 may be involved in the pathophysiology of endometriosis and related infertility. [Copyright &y& Elsevier]

Abstract: Interleukin-1 (IL1) is believed to play a central role in the immuno-inflammatory process associated with endometriosis. IL1 triggers cell activation via its receptor type I (IL1R1), but its receptor type II (IL1R2) is known instead as a scavenger that buffers the cytokine''s effects. Our previous studies have shown increased expression of IL1R1 in active endometriotic implants compared to normal and endometriosis women-derived endometrial tissues, and a simultaneous decrease in IL1R2 expression at the protein level. In the present study, in situ hybridization demonstrated a noticeable decrease in IL1R2 mRNA hybridization score in eutopic and matched ectopic endometrial tissues of women with endometriosis compared to normal women in the stroma (P <0.001 and P <0.001, respectively) and the epithelium (P <0.01 and P <0.05, respectively), whereas IL1R1 mRNA hybridization score was higher only in the ectopic implants, with a statistically significant difference in the stroma (P <0.05). This was corroborated by RT-PCR analysis of IL1R1 and IL1R2 mRNAs in ectopic (P <0.05 and P <0.05, respectively) and matched eutopic (P =0.22 and P <0.05, respectively) endometrial tissues from women with endometriosis compared to endometrial tissues from normal women. The decrease in IL1R2 mRNA levels in eutopic endometrial tissue of endometriosis women, and the concomitant increase in IL1R1 mRNA levels in ectopic implants, reveal a profound defect in IL1R 1 and IL1R2 gene expression which may accentuate the capability of this tissue to respond to IL1 and favor its ectopic growth. [Copyright &y& Elsevier]

Abstract: This study builds upon the established genetic control of antimalarial immune responses and prior association studies by using a family-based approach, transmission disequilibrium testing, to identify immune response genes that influence antibody responses to Plasmodium falciparum infection in an endemic Tanzanian population. Candidate polymorphisms are within the interleukin-1 (IL-1) gene cluster, the IL-10 promoter, Major histocompatibility complex class II and III, the 5q31-q33 region, and the T-Cell Receptor beta variable region. There was a significant association between the IL1RN alleles and total IgE. Weak evidence for association was present between polymorphisms in the IL10 promoter region and both anti-P falciparum IgE and IgG4 antibodies. [Copyright &y& Elsevier]

Receptor-interacting protein 2 (RIP2) is a member of the RIP kinase family that has been shown to be crucially involved in inflammation, innate and adaptive immune responses. The physiological and pathological roles of RIP2 are mediated through its involvement in multiple NF-κB activation pathways, including those triggered by tumor necrosis factor (TNF), interleukin 1 (IL-1), Toll-like receptor 2 (TLR2), TLR3, TLR4 and Nod1. In this report, we identified the LIM-domain-containing protein TRIP6 as a RIP2-interacting protein in yeast two-hybrid screens. In mammalian cells, TRIP6 interacts with RIP2 in a TNF- or IL-1-dependent manner. Overexpression of TRIP6 potentiates RIP2-mediated NF-κB activation in a dose-dependent manner. The LIM domains of TRIP6 are responsible for its interaction with RIP2. TRIP6 also interacts with TRAF2, a protein that is crucially involved in TNF signaling, as well as the IL-1 receptor, TLR2 and Nod1. Overexpression of TRIP6 potentiates NF-κB activation by TNF, IL-1, TLR2 or Nod1, whereas a dominant negative mutant or RNA-interference construct of TRIP6 inhibits NF-κB activation by TNF, IL-1, TLR2 or Nod1. Moreover, TRIP6 also potentiates RIP2- and Nod1-mediated ERK activation. These data have established a physical and functional association between TRIP6 and RIP2, and suggest that RIP2's involvement in multiple NFκB and ERK activation pathways is mediated through TRIP6. [ABSTRACT FROM AUTHOR]