European cytokine network最新文献

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.

Infertility, which increased worldwide over the past few decades, has recently been linked to obesity prevalence. Adipokines, produced by adipose tissue, could be the link between obesity and infertility. The association between circulating adipokines and female infertility has been extensively studied in the last ten years. However, the male aspect has been less investigated, although some adipokines are present in seminal plasma. We have attempted to analyze published studies that measured seminal plasma adipokines and their relationships with semen parameters. Apart from leptin, other seminal adipokines have rarely been studied. Indeed, leptin seems to have a differential role depending on its concentration in the seminal plasma. Thus, it could have a beneficial effect at lower concentrations but a deleterious effect at higher seminal levels. Although some studies are currently available, the roles of leptin and other adipokines in seminal plasma on sperm parameters and their consequences on male fertility remain to be clarified.

Mice infected with mouse hepatitis virus A59 (MHV-A59) develop hepatitis and autoantibodies (autoAb) to liver and kidney fumarylacetoacetate hydrolase (FAH), a fact closely related to the release of alarmins such as uric acid and/or high-mobility group box protein 1 (HMGB1). We studied the effect of neutralizing monoclonal antibodies (MAb) against IL-17A in our model of mouse MHV-A59-infection. MAb anti-IL-17F and anti-IFNγ were used to complement the study. Results showed that transaminase levels markedly decreased in MHV-A59-infected mice treated with MAb anti-IL-17A whereas plasmatic Ig concentration sharply increased. Conversely, MAb anti-IL-17F enhanced transaminase liberation and did not affect Ig levels. Serum IFNγ was detected in mice infected with MHV-A59 and its concentration increased after MAb anti-IL-17A administration. Besides, MAb anti-IFNγ greatly augmented transaminase plasmatic levels. IL-17A neutralization did not affect MHV-A59-induction of HMGB1 liberation and slightly augmented plasmatic uric acid concentration. However, mice treated with the MAb failed to produce autoAb to FAH. The above results suggest a reciprocal regulation of Th1 and Th17 cells acting on the different MHV-A59 effects. In addition, it is proposed that IL-17A is involved in alarmins adjuvant effects leading to autoAb expression.

Toll-like receptor (TLR) agonists drive hematopoietic stem and progenitor cells (HSPCs) to differentiate along the myeloid lineage in vitro and also in vivo following infection. In this study, we used an in vitro model of HSPC differentiation to investigate the functional consequences (cytokine production) that exposing HSPCs to various pathogen-associated molecular patterns (PAMPs) and Candida albicans cells have on the subsequently derived macrophages. Mouse HSPCs (Lin^- cells) were cultured with GM-CSF to induce macrophage differentiation in the presence or absence of the following pattern recognition receptor (PRR) agonists: Pam₃CSK₄ (TLR2 ligand), LPS (TLR4 ligand), depleted zymosan (which only activates Dectin-1), or inactivated C. albicans yeasts (which activate several PRRs, mainly TLR2 and Dectin-1). Our data show that only pure TLR2 ligand exposure (transient and continuous) impacts the inflammatory function of GM-CSF-derived macrophages, because Pam₃CSK₄-exposed HSPCs generate macrophages with a diminished ability to produce inflammatory cytokines. Interestingly, the Pam₃CSK₄-induced tolerance of macrophages (by transient exposure of HSPCs) is reinforced by subsequent exposure to C. albicans cells in GM-CSF-derived macrophages; however, the induced tolerance is partially reversed in M-CSF-derived macrophages. Therefore, the ability of macrophages to produce inflammatory cytokines is extremely dependent on how the HSPCs from which they are derived receive and integrate multiple microenvironmental signals (PRR ligands and/or CSFs).

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting nearly 1% of adults worldwide. This study aimed to investigate whether sophocarpine is a potential drug for treating RA. The cytotoxicity of sophocarpine to RA-fibroblast-like synoviocytes (FLSs) was evaluated using 3-[4,-dimethylthiazol-2-y]-2,5-diphenyl-tetrazolium bromide (MTT) assays kit and released lactate dehydrogenase (LDH) assays. The transcription of proinflammatory cytokines in RA-FLSs was analyzed by reverse transcription and real-time polymerase chain reaction (RT-PCR). The proteins levels were further verified by enzyme-linked immunosorbent assay (ELISA). The alterations in the mediators of mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways were tested by western blotting. The clinical effects of sophocarpine were evaluated in type II collagen-induced arthritis (CIA) in DBA-/1 mouse model by scoring their clinical responses, synovitis, and cartilage destructions, and ELISA was employed to analyze the concentrations of proinflammatory cytokines in the serum of CIA mice. The results showed that sophocarpine contained low cytotoxicity to RA-FLS cells, and it was capable to downregulate the expressions of LPS-induced proinflammatory cytokines. The suppressions of MAPK and NF-κB signaling pathways by sophocarpine were also found in LPS-induced RA-FLSs. The attenuation of the symptoms in CIA mouse model were significant, in which concentrations of proinflammatory cytokines were decreased after the sophocarpine treatment. In this study, we demonstrated the potential of sophocarpine in treating RA, both in vitro and in vivo. Sophocarpine may be a potential drug in treating human RA.

The purpose of this study was to evaluate T-cell immunity markers using serial post-transplantation monitoring of cytokine-producing cells during the first post-transplant months for the prediction of acute rejection and potentially chronic rejection of kidney allograft. We followed 57 kidney allograft recipients for meanly 3 years post-transplantation. Blood samples were collected pre-transplant, 2, 4 and 12 weeks post-transplant. The frequencies of IL-10-, IL-17- and IFN-γ-producing cells were determined in all time-points using ELISPOT assay. The results of ELISpot monitoring and levels of IL-23 and TGF-β were compared between recipients with acute (n = 12) or chronic rejection episodes and patients with stable graft function (n = 45). In all post-transplant time-points, significantly high frequencies of IFN-γ- and IL-17-producing cells and low frequency of IL-10-producing cells were observed in rejection group versus patients with stable graft function (P < 0.0001). The ROC curve analysis for determining the reliability of cytokine-producing cells for the prediction of acute rejection revealed that AUC was 0.046 for IL-10 (P < 0.001), 0.927 for IL-17 (P < 0.001) and 0.929 for INF-γ-producing cells (P < 0.001). Our results indicate that analyzing the frequencies of INF-γ/IL-10/IL-17-producing cells may define a reliable panel for the prediction of acute rejection within the first post-transplant year which could also be applicable for the prediction of chronic rejection episodes.

Skin is a complex organ and the largest interface of the human body exposed to numerous stress and pathogens. Skin is composed of different cell types that together perform essential functions such as pathogen sensing, barrier maintenance and immunity, at once providing the first line of defense against microbial infections and ensuring skin homeostasis. Being inoculated directly through the epidermis and the dermis during a vector blood meal, emerging Dengue, Zika and West Nile mosquito-borne viruses lead to the initiation of the innate immune response in resident skin cells and to the activation of dendritic cells, which migrate to the draining lymph node to elicit an adaptive response. This literature review aims to describe the inflammatory response and the innate immune signalization pathways involved in human skin cells during Dengue, Zika and West Nile virus infections.

Lyme disease is a zoonosis caused by infection with bacteria belonging to the Borrelia burgdorferi species after the bite of an infected tick. Even though an infection by this bacterium can be effectively treated with antibiotics, when the infection stays unnoticed B. burgdorferi can persist and chronic post-treatment Lyme disease syndrome is able to develop. Although a cellular and humoral response is observed after an infection with the Borrelia bacteria, these pathogens are still capable to stay alive. Several immune evasive mechanisms have been revealed and explained and much work has been put into the understanding of the contribution of the innate and adaptive immune response. This review provides an overview with the latest findings regarding the cells of the innate and adaptive immune systems, how they recognize contribute and mediate in the killing of the B. burgdorferi spirochete. Moreover, this review also elaborates on the antigens that are expressed by on the spirochete. Since antigens drive the adaptive and, indirectly, the innate response, this review will discuss briefly the most important antigens that are described to date. Finally, there will be a brief elaboration on the escape mechanisms of B. burgdorferi with a focus on tick salivary proteins and spirochete antigens.

IL-1R8, also known as SIGIRR or TIR8, is a trans-membrane protein belonging to the IL-1 receptor family. The human gene includes ten exons, and alternative splicing can result in different isoforms. We, herein, characterized a longer isoform of IL-1R8 containing an in-frame additional sequence between the TIR domain and the C-terminal portion of the protein. IL-1R8 Long (IL-1R8L1) mRNA was specifically expressed and regulated in distinct cell lines, in a manner similar to the classic isoform. Overexpression of IL-1R8L1 resulted in the production of a corresponding protein that showed a pattern of cell localization similar to the classic isoform. An antibody directed against an IL-1R8L1 specific peptide, detected this novel isoform in different cell lines and tissues where this protein may complement the anti-inflammatory functions of classic IL-1R8.