European cytokine network最新文献

The prevalence of obesity has recently increased dramatically and has contributed to the increasing prevalence of various pathological conditions, including type 2 diabetes mellitus, nonalcoholic fatty liver disease, asthma, various types of cancer, cardiovascular and neurodegenerative diseases, and others. Accumulating evidence points to localized inflammation in adipose tissue, which, in turn, promotes systemic low-grade inflammation as a primary force contributing to the development of these pathologies. A better understanding of the underlying mechanisms behind obesity-induced adipose tissue inflammation is required to develop effective therapeutic or prophylactic strategies. This review is aimed to present the current knowledge of adipose tissue inflammation associated with obesity.

Leptin may support the proliferation and hinder the apoptosis of tumor cells. Although leptin expression has been studied in several human tumors, its potential clinical significance remains uncertain in patients with gastric carcinoma. Furthermore, the majority of available findings have been determined from preclinical studies using stomach carcinoma tissue section and, to date, few studies have evaluated the clinical significance of leptin in the serum or plasma of gastric carcinoma patients. In the current study, the serum concentration of soluble leptin was assessed in gastric carcinoma patients, and its contributions to the clinical parameters and prognosis of patients were determined. A total of 63 pathologically confirmed gastric cancer patients and 30 healthy subjects were enrolled in the study and circulating leptin levels in the serum of all subjects were determined by ELISA. The serum leptin concentrations were significantly lower in the gastric cancer patients compared with the healthy control group (P = 0.009). In the gastric cancer patients, the clinical features of patient age, sex, lesion localization, histopathology, pathological grade, stage of disease, and serum tumor markers including lactate dehydrogenase, carcinoembryonic antigen, and carbohydrate antigen 19-9 were not correlated with serum leptin concentration. Furthermore, no association was observed between serum leptin concentration and responsiveness to chemotherapy (P = 0.51), and leptin level had no apparent prognostic role in clinical outcome (P = 0.57). In conclusion, although it was not predictive or prognostic, serum leptin level may be a valuable diagnostic indicator in patients with gastric carcinoma.

Interleukin-6 (IL-6) expression and secretion, induced by inflammatory processes, stimulate the acute phase response cascade. The overexpression of IL-6 contributes to a variety of inflammatory diseases, e.g. rheumatoid arthritis, Castleman's disease, multiple myeloma, and prostate cancer. Screening for high amounts of IL-6 in the patients' blood serum can be crucial for an adequate treatment. In this study, five novel murine monoclonal antibodies (mAbs) reactive to human IL-6 were generated. The mAbs were characterized for potential diagnostic purposes and recombinant antibodies were derived thereof. Initial epitope mapping using a combination of blocking experiments and Hyper-IL-6, a fusion protein consisting of IL-6 and the soluble IL-6 receptor revealed distinct but overlapping binding sites. At least one of the mAbs was found to interact with the region of IL-6/ IL-R complex formation. Three mAbs were applied successfully in intracellular staining by flow cytometry, whereas one of the mAbs showed comparable binding as a reference reagent. Furthermore, the mAbs were tested for applications in various immunological assays such as ELISA, Western blot and surface plasmon resonance spectroscopy (SPR), using IL-6 from commercial sources as well as in-house produced protein (IL-6_IME). The limit of detection was determined by sandwich ELISA (0.5 ng/mL, SD ±0.005). Our results also demonstrated that the recombinant IL-6 produced was functional and correctly folded. These findings support the use of the generated mAb clones as promising candidates for application in various immunological assays for diagnostic and scientific purposes.

Since pro-inflammatory cytokine IL-18 and its receptor (IL-18R) are closely involved in regulating both adaptive and innate immune responses, it is conceivable that they might play an important role in organ transplantation. IL-18 can stimulate lymphocytes to produce the IFN-γ and regulate macrophage activity, thereby increasing the expression of proinflammatory cytokines including IL-1β, IL-6, CCL4 (macrophage inflammatory protein-1 β), CXCL2 (macrophage inflammatory protein-2), and CCL2 (monocyte chemotactic protein-1). Nevertheless, the IL-18 signaling pathway and its underlying mechanisms remain obscure in transplant biology. This review is to summarize recent advances in our knowledge about the IL-18 signaling pathway and to analyze their functions in transplant-related biology. It was found that IL-18/IL-18R signaling pathway contributed to vascular transplantation, ischemmia/reperfusion, acute kidney injury, and acute rejection of kidney/liver/heart transplantation. IL-18 was a potential CYP3A expression modulator and was capable of affecting tacrolimus pharmacokinetics. Neutralizing IL-18 by its inhibitor IL-18 binding protein could efficiently suppress the production of injury-associated cytokines such as IL-6, TNF-α, IFN-γ, CXCL10 (IFN-γ-inducible protein10), and CX₃CL1 (fractalkine) and improve allograft function. Blockade of IL-18 signaling could regulate cardiomyocyte apoptosis and inhibit Th17 cells differentiation. Alteration of IL-18 levels was suggested as a biomarker for predicting ongoing allograft outcome. All these activities could deepen our understanding of immunobiological role of IL-18 and its receptor in the field of organ transplantation. Intervention of IL-18 signaling pathway might be utilized as a therapeutic strategy in clinic.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joints inflammation. One of the aggressive characteristics of RA fibroblast-like synoviocytes (FLS) is the tendency for migration in the local environment, which plays a central role in the RA pathogenesis. Tumor Necrosis Factor (TNF)-like cytokine 1A (TL1A) is a member of TNF superfamily, which has a role in autoimmunity and influences the RA-FLS behavior through TNF receptor 2 (TNFR2). We investigated the effect of TNF-like cytokine 1A (TL1A) on RA-FLS migration using patients' samples. Specifically, we examined the hedgehog signaling pathway which is a key regulator in chondrocyte growth and differentiation. We found that TL1A increased significantly the hedgehog homologue Indian hedgehog (IHH) and its receptor Patched 1, 2 (PTCH 1, 2) in RA-FLS. In addition, TL1A-stimulated RA-FLS promoted significantly IHH protein expression. However, both mRNA and protein levels decreased substantially after blocking TL1A with TNFR2 antagonist. The migratory property of RA-FLS was enhanced after stimulation of RA-FLS with TL1A, but was compromised following TL1A blockage. In conclusion, our study has revealed that TL1A modulated RA-FLS migration and Indian hedgehog signaling pathway using TNFR2.

Interleukin-32 (IL-32) is an inflammatory cytokine produced mainly by T, natural killer, and epithelial cells. Previous studies on IL-32 have primarily investigated its proinflammatory properties. The IL-32 also has been described as an activator of the p38 mitogen-activated protein kinase (MAPK) and NF-κB, and induces several cytokines. In this study, we hypothesized that the inflammatory regulators NF-κB, MAP kinase, STAT1, and STAT3 are associated with the expression of the IL-32 protein in human calcified aortic valve cells. This study comprised aortic valve sclerotic patients and control group patients without calcified aortic valve. Increased IL-32 expression in calcified aortic valvular tissue was shown by immunohistochemical staining and western blotting. There was an increase in NF-κB p65 level, p-ERK, p-JNK, and p-p38 MAPK activation underlying IL-32 expression in the study. The level of p-STAT3 but not p-STAT1 was found to be increased in calcified aortic valve tissue. In cultured primary human aortic valve interstitial cells, inhibition of NF-κB or MAPK kinase pathways results in a decrease of IL-32 expression. Treatment of recombinant IL-32 induced the levels of TNF-α, IL-6, IL-1β, and IL-8. Our findings demonstrate that IL-32 may be an important pro-inflammatory molecule involved in calcific aortic valve disease.

Interleukin (IL)-6 is a pleiotropic inflammatory cytokine with both pro- and anti-inflammatory capacities, produced by different cells and tissues, such as leukocytes, adipocytes, and endothelium. From the viewpoint of cardiologists, this cytokine is a reliable biomarker of cardiac dysfunction, occurrence of atrial fibrillation, cardiac myxoma with recurrence, remote metastasis or embolization, and atherosclerotic processes. Although IL-6 levels were detected in patients undergoing cardiac operations and reported sporadically, the perioperative kinetics of IL-6 in cardiac surgical patients was insufficiently elaborated. The influencing factors, clinical implications, and causative effects of IL-6 on clinical outcomes and potential treatment choices among cardiac surgical patients remained to be clarified as well. The purpose of this article is to discuss these aspects of IL-6 in patients undergoing a cardiac operation.

Background: Cytokine genes, including interleukin-10 (IL-10), are known to play important roles in the pathogenesis of juvenile idiopathic arthritis (JIA). This study aims to determine whether the IL-10 polymorphisms confer susceptibility to JIA.

Methods: A meta-analysis was performed on the associations between the IL-10 -1082 G/A, -592 C/A, and -819 C/T polymorphisms and JIA. A total number of 7 studies involving 1,785 patients and 6,142 controls were considered in the meta-analysis.

Results: Meta-analysis of the IL-10 -592 C/A and -819 C/T polymorphisms showed no association with JIA in the study participants, or in Caucasian or Middle Eastern participants. Meta-analysis of the IL-10 -1082 A allele in all study participants, Caucasian and Middle Eastern, showed significant associations with RA (overall ORs were 1.17, 1.15, and 1.41, respectively). Meta-analysis of the AA versus GG genotype of the IL-10 -1082 G/A polymorphism revealed significant associations with JIA (OR = 3.66, 95% CI = 1.44-9.29, P = 0.006) in participants from Middle Eastern countries. Additionally, meta-analysis of the GG versus AA+GA genotypes of the IL-10 -1082 G/A polymorphism revealed the GG genotype as the protective factor against JIA in the Middle Eastern subgroup (OR = 0.44, 95% CI = 0.20-0.94, P = 0,04). Moreover, meta-analysis of the IL-10 -1082 A allele in 4 studies on Hardy-Weinberg equilibrium showed a significant association with JIA (OR = 1.17, 95% CI = 1.07-1.28, P = 0.0009). No association was found between the IL-10 (-1082, -819, -592) ACC, ATA, and GCC haplotypes and JIA.

Conclusions: These results suggest that the IL-10 -1082 G/A polymorphism confers susceptibility to JIA.

There is increasing evidence for the importance of immunity in breast cancer. IFNγ is expected to have a prognostic value based on its major role in innate and specific cell-mediated immunity. In this retrospective study, based on the 14-year follow-up of 73 patients with breast cancer after surgery and radiotherapy but no subsequent systemic therapy, we investigated the prognostic time dependence of intra-tumoural IFNγ mRNA and protein levels. Over the entire 14 years of follow-up, neither IFNγ mRNA nor protein was significantly associated with metastasis outcome by AUC and Cox regression criteria. However, evaluation of the shorter periods has revealed a prognostic significance in the late follow-up period of 7-14 years for IFNγ mRNA and protein with the maximal respective AUCs of 0.72 and 0.73 and hazard ratios of 6.1 and 5.2, respectively. Interestingly, the opposite prognostic association was discovered for IFNγ mRNA and protein in the first 7 years of follow-up, possibly due to the negative correlation of IFNγ protein and mRNA. Moreover, the prognostic association of IFNγ mRNA has shifted from marking the favourable outcome in the first 7 years to poor outcome thereafter. This study contributes to clarification of the previously inconsistent prognostic performance of IFNγ by providing the first prognostic evaluation with long follow-up, time-dependence assessment and absence of any chemotherapy influence.

Interleukin (IL)-18, structurally similar to IL-1β, is a member of IL-1 superfamily of cytokines. This cytokine, which is expressed by many human lymphoid and nonlymphoid cells, has an important role in inflammatory processes. The main function of IL-18 is mediated through induction of interferon-γ (IFN-γ) secretion from T helper (Th1) cells. This cytokine synergistically with IL-12 contributes to Th1 differentiation and, therefore, is important in host defense mechanisms against intracellular bacteria, viruses, and fungi. Recent evidences showing the involvement of IL-18 in Th2 differentiation and ultimately IgE production from B cells have shed a new insight on the dual effects of IL-18 on Th1 and Th2 inflammatory responses. IL-18 in combination with IL-12 can activate cytotoxic T cells (CTLs), as well as natural killer (NK) cells, to produce IFN-γ and, therefore, may contribute to tumor immunity. The biological activity of IL-18 is not limited to these cells, but it also plays a role in development of Th17 cell responses. IL-18 synergistically with IL-23 can induce IL-17 secretion from Th17 cells. The diverse biological activity of IL-18 on T-cell subsets and other immune cells has made this cytokine a good target for investigating its role in various inflammatory-based diseases. Lately, the discovery of IL-18 binding protein (IL-18BP), a physiological inhibitor of IL-18 and a hallmark of IL-18 biology, made this cytokine an attractive target for studying its pros and cons in the treatment of various diseases. In recent years, the biology, genetics, and pathological role of IL-18 have been studied in a number of diseases. In this article, we aimed to present an updated review on these aspects regarding the contribution of IL-18 to important diseases such as cancer, autoimmunity, and inflammatory-mediated conditions including allergic diseases, metabolic syndrome, and atherosclerosis. Emerging data indicating prognostic, diagnostic, and therapeutic features of IL-18 and its related molecules will also be discussed.