IL-37 Regulates Expression Of Key Cytokines And Modulate T-cell-priming Function Of Dendritic Cells

Background:Dendritic cells (DCs) can be efficiently processing and presenting antigen, which is the most powerful antigen presenting cells. DCs is capable of capturing, processing and handling antigen.and then submitting it to the T and B lymphocytes and activates lymphocytes, which can induce a series of immune response, and play starting roles in cellular immune response in the body. Lipopolysaccharide (LPS) is a major component of the cytoderm of gram negative bacteria, can induce cells to produce inflammatory reaction. TNF-a secretion in the inflammatory phase, significantly promote the proliferation of T cells, enhance the killing effect. The expression of IL-6 can weaken the neutrophils phagocytosis ability, intensify the production of inflammatory mediators, and accelerate the process of inflammation reaction further. When inflammation occurs, LPS can bind cell surface marker CD14, and promote the secretion of inflammatory factors, which mediate a series of biological reaction. Currently,IL-37 is the only homologue of IL-1 family members which did not find in the rat. IL-37 was expressed In the bone marrow, liver, thymus, lung and other tissues. IL-37 is involved in many development inflammatory and immunological diseases. In natural killer cells and mononuclear cells, IL-37 can combine IL-18BP and formed a complex with the IL-18R beta,which inhibit the activity of IL-18, and inhibited producing inflammatory factor IFN-gamma.However, IL-37 of DCs and its role in the mechanism of action of immune and infectious diseases is not clear. The influence and role in the inflammation of IL-37 expression on DCs of inflammatory factors need further study.Objective:This study was aimed to investigate the effects of IL-37(interleukin-37, IL-37) on regulating inflammatory cytokines of Lipopolysaccharides (LPS) treated DCs.Methods:Mice bone marrow cells were taken and induced the differentiation to dendritic cells (DCs).DCs were sorted with immunomagnetic bead and stimulated by LPS with or without 37.The expression of CD80, CD86 were detected by Flow cytometry; the inflammation related genes were detected by real-time PCR.the expression of inflammatory cytokines were detected by Cytometric Beads Array(CBA).Results:After the stimulated by LPS, the co-stimulating molecules of IL-37 treated DCs were inhibited by the depressed expression of CD80, CD86. The cytokines TNF-a, IL-6, IL-1 a were also reduced in the expression of mRNA and proteins.Conclusion:It is concluded that IL-37 plays a critical in inhibiting expression of CD80, CD86 and inflammatory cytokines, this effects may be related with the balance of the inflammatory factor network, thus inhibiting immune responses.Background: Dendritic cells(DCs) constitute a rare cell population present most tissues at a frequency ranging from 0.1 to 2% of the 1:otal cell number. DCs are prossicmal antigen presenting cells(APCs),which flmctio in performing a key role in activation of immune response by capturing, processing, presenting antigens and activating naive T cells. Under steady-state conditions, DCs maintain an immature status until an nflammatory signal promo化s their activation,at which time they up egulate costimulatory markers or humoral factor such as CD80, CD86, and CD40 and facilitate Tcellactivationandproliferation.Cytokines of the interleukin(IL)-l family is family of protein molecules that possees variety of immunoregulatory properties response to inflammation and autoimmune diseases. They act the first line of defense against pathogenic micro-organisms and physical damage/stress. IL-37,the recently identified IL-1family,originally defined as IL-1 family member 7(IL-1F7),is a ftmdamental inhibitor of innate immunityIL-37 is expressed a variety of normal tissues and tumors. Kumar and colleagues have identified IL-3 7 protei expression in nsils,skin, esophagus, placenta, and melanoma as well as carcmomas of the breast prostate,colon,and lung, albeit at low levels. It can also be induced in peripheral blood mononuclear cells(PBMCs) and dendritic cells.Despe extensive database arches and isequencing of the IL-37-gee locus,murine homologue of IL-1F7 has yet been found. Recently,McNamee et alported that human IL-37 transgenic mice were protected from dextran sulphate sodium(DSS)colitis.Although many studies have revealed the anti-inflammatory behavior of IL-37,ere is scant information about IL-37 on tinction of DC.Objective: This study was aimed inveigate the phenotype and function of DC IL-37 on immune characteristics and CD4+ 了 cells and CD8+T cells, which can further explain IL-37 in immxine diseases.Methods: Mice bone marrow cells were taken and induced the differentiation to dendritic cells(DCs). After treated with IL-37, flow cytometry was detect cell surface costiimilatory molecules(CD80,CD86,CD40) and detection of tumornecrosis facthr a(TNF-a), interleukin 6 yL-6), int:erleukin 10(7L-10),and transforming growth fkctor P(TGF-3) mRNA expression were used with IT-PC I.The expiession of TNF- cell supernatant IL-6,IL-10 alpha and TGF- beta protein was deteckd by quantitative Cy1:ometric Beads Array(CBA) or ELISA kit. Western Blot and flow cytometry weie used 1:0 de1:ect 1;he expiression of p-ERKl/2,p-S6 K and p-NF- K B in dedritic cells. Expiession of inflammatory cytokines was deteded by pro1:einhibUers. Cell size, CFSE proliferation profile,and expression of activation marker CD25 and CD69 were analyzed by flow cytometry.Results: IL-37 downregulated the expression of CD80 and CD86, which Wei’S dendritic cell surface costimulatory molecules. At the same time, the expression of pro-inflammatory cytokines TNF- a ad IL-6 was significantly inhited. and T cell suppressor fac1;or TGF increased signicantly. T cells proliferation and activation was significantly decreased by IL-37 treated dendritic cells. IL-37 can reduce tibe expression of phosphorylated ERK,NF-kB and S6 K iin dendritic cells. The activation and proliferation of CD4+ and CD8+ T cells were all inWbked as determined by decreased cell size(FSC),and also reduced expression of surface markers CD25 and CD69,and CFSE dilution.Conclusion: It is concluded at the maturation and immue activation of DC may affect by IL-37 through the ERK,NF-kB and S6K signal pathway, which inbit activation and proliferation of T cells.