Suppression Of IL-17 Production Research Articles

PARP2 downregulation in T cells ameliorates lipopolysaccharide-induced inflammation of the large intestine.

T cell-dependent inflammatory response with the upregulation of helper 17 T cells (Th17) and the downregulation of regulatory T cells (Treg) accompanied by the increased production of tumor necrosis alpha (TNFa) is characteristic of inflammatory bowel diseases (IBD). Modulation of T cell response may alleviate the inflammation thus reduce intestinal damage. Poly(ADP-ribose) polymerase-2 (PARP2) plays role in the development, differentiation and reactivity of T cell subpopulations. Our aim was to investigate the potential beneficial effect of T cell-specific PARP2 downregulation in the lipopolysaccharide (LPS) induced inflammatory response of the cecum and the colon. Low-dose LPS was injected intraperitoneally to induce local inflammatory response, characterized by increased TNFa production, in control (CD4Cre; PARP2+/+) and T cell-specific conditional PARP2 knockout (CD4Cre; PARP2f/f) mice. TNFa, IL-1b, IL-17 levels were measured by ELISA, oxidative-nitrative stress was estimated by immunohistochemistry, while PARP1 activity, p38 MAPK and ERK phosphorylation, and NF-kB expression in large intestine tissue samples were examined by Western-blot. Systemic & local T cell subpopulation; Th17 and Treg alterations were also investigated using flowcytometry and immunohistochemistry. In control animals, LPS induced intestinal inflammation with increased TNFa production, while no significant elevation of TNFa production was observed in T cell-specific PARP2 knockout animals. The absence of LPS-induced elevation in TNFa levels was accompanied by the absence of IL-1b elevation and the suppression of IL-17 production, showing markedly reduced inflammatory response. The increase in oxidative-nitrative stress and PARP1-activation was also absent in these tissues together with altered ERK and NF-kB activation. An increase in the number of the anti-inflammatory Treg cells in the intestinal mucosa was observed in these animals, together with the reduction of Treg count in the peripheral circulation. Our results confirmed that T cell-specific PARP2 downregulation ameliorated LPS-induced colitis. The dampened TNFa production, decreased IL-17 production and the increased intestinal regulatory T cell number after LPS treatment may be also beneficial during inflammatory processes seen in IBD. By reducing oxidative-nitrative stress and PARP1 activation, T cell-specific PARP2 downregulation may also alleviate intestinal tissue damage.

The suppression of IL-17 production from T cells by gallate-type procyanidin is mediated by selectively inhibiting cytokine production from dendritic cells

Abnormal T helper 17 (Th17) responses promote inflammation and cause inflammatory diseases. Natural components that modulate Th17 functions can be effective for the amelioration of inflammatory diseases. Procyanidin B2 3,3''-di-O-gallate (PCB2DG) contained in grape seeds markedly suppressed interleukin (IL)-17 production from spleen cells but not CD4+ T cells. The aim of this study was to elucidate the mechanisms by which PCB2DG suppresses IL-17. Our results showed that PCB2DG suppressed the production of IL-17, tumor necrosis factor (TNF)-α, IL-1β, and IL-6 with the suppression of transcription factors expression. In addition, we revealed that TNF-α and IL-1β were required to induce IL-17 production in this experimental condition, and PCB2DG suppressed these cytokines from dendritic cells (DCs). Furthermore, CD4-DC co-culture experiments showed that the production of IL-17, TNF-α, and IL-1β was markedly inhibited in co-cultures of PCB2DG-pretreated CD4+ T cells and DCs. These results suggested that PCB2DG first modulated TNF-α production by CD4+ T cells and then suppressed IL-1β secretion from DCs, resulting in decreased IL-17 production. Thus, PCB2DG can control the cytokine network associated with Th17 cells, providing a novel mechanism underlying the immunosuppressive effects of polyphenols.

Identification of duck IL-4 and its inhibitory effect on IL-17A expression in R. anatipestifer-stimulated splenic lymphocytes

As the dysregulation of IL-17 is implicated in the pathogenesis of various autoimmune and inflammatory diseases, the suppression of IL-17 production by Th2 cytokines could alleviate the development of these diseases. Previously, we confirmed that inflammatory cytokines including IL-17A are strongly associated with R. anatipestifer infection, which is one of the most important bacterial pathogens in the duck industry. Here, we found that IL-4 treatment downregulated the expression of IL-17A and IL-17F transcripts in splenic lymphocytes stimulated with R. anatipestifer. Moreover, duck IL-4 (duIL-4) treatment in R. anatipestifer-stimulated lymphocytes suppressed the expression of IL-23p19 and IL-12p40 transcripts compared to untreated and stimulated lymphocytes. Conversely, duIL-4 increased levels of IFN-γ and IL-10. We identified a full-length duIL-4 cDNA encoding 136 amino acids from ConA-activated splenic lymphocytes that shares 49.3–50% amino acid sequence identity with chicken and quail IL-4 and 21–29.7% with mammalian and piscine homologues. Low or moderate levels of duIL-4 transcript were observed in healthy tissues, including the spleen, bursa, and thymus, whereas duIL-4 expression was higher in the kidney and lung. Levels of duIL-4 were generally upregulated in mitogen-activated splenic lymphocytes but lower in the liver and spleen of R. anatipestifer-infected ducks compared to those of infected chickens. Recombinant duIL-4 promoted nitric oxide synthesis in duck macrophages stimulated by R. anatipestifer compared to untreated and stimulated control macrophages. These results demonstrate that IL-4 is an important Th2 cytokine that inhibits inflammatory responses in splenic lymphocytes stimulated with R. anatipestifer.

Human β-defensin-2 enhances IFN-γ and IL-10 production and suppresses IL-17 production in T cells

Psoriasis is an inflammatory dermatosis with enhanced expression of hBD-2 in keratinocytes and infiltration of cytokine-producing T cells, which in turn, up- or down-regulate hBD-2 expression. We determined the serum levels of hBD-2 and cytokines in psoriasis patients and analyzed the effects of hBD-2 on cytokine production in human peripheral blood T cells. Serum hBD-2 levels in patients were higher than those in controls and correlated with PASI, serum IFN-γ, and IL-10 levels and correlated inversely with serum IL-17 levels. IFN-γ, IL-17, IL-22, TNF-α, IL-1β, and IL-6 enhanced, and IL-10, IL-4, and IL-13 suppressed hBD-2 secretion from keratinocytes. hBD-2 enhanced secretion and mRNA levels of IFN-γ, TNF-α, IL-10, IL-1β, IL-6, and IL-22 and reduced those of IL-17 in CD3/28-stimulated T cells. These effects of hBD-2 were counteracted by PTX. hBD-2 induced phosphorylation of JNK, ERK, and Akt in T cells. Inhibitors of these signals attenuated hBD-2-induced production of IFN-γ, TNF-α, IL-10, IL-1β, IL-6, and IL-22. hBD-2 suppressed phosphorylation of STAT3 and enhanced expression of SOCS3 in CD3/28-stimulated T cells. siRNA against SOCS3 reversed hBD-2-induced suppression of IL-17 production and STAT3 phosphorylation. JNK and MEK inhibitors suppressed hBD-2-induced expression of SOCS3. In conclusion, hBD-2 may bind PTX-sensitive GPCR(s) on T cells and act as a stimulator by enhancing IFN-γ, TNF-α, IL-1β, IL-6, and IL-22 production via JNK, MEK/ERK, and PI3K/Akt and as a regulator by suppressing IL-17 production via SOCS3 or by stimulating IL-10 production.

Interleukin (IL)‐21‐independent pathogen‐specific CD8+ T‐cell expansion, and IL‐21‐dependent suppression of CD4+ T‐cell IL‐17 production

Although interleukin-21 (IL-21) potently activates and controls the differentiation of immune cells after stimulation in vitro, the role for this pleiotropic cytokine during in vivo infection remains poorly defined. Herein, the requirement for IL-21 in innate and adaptive host defence after Listeria monocytogenes infection was examined. In the innate phase, IL-21 deficiency did not cause significant defects in infection susceptibility, or in the early activation of natural killer and T cells. In the adaptive phase, L. monocytogenes-specific CD8(+) T cells expand to a similar magnitude in IL-21-deficient mice compared with control mice. Interestingly, the IL-21-independent expansion of L. monocytogenes-specific CD8(+) T cells was maintained even in the combined absence of IL-12 and type I interferon (IFN) receptor. Similarly, L. monocytogenes-specific CD4(+) T cells expanded and produced similar levels of IFN-γ regardless of IL-21 deficiency. Unexpectedly however, IL-21 deficiency caused significantly increased CD4(+) T-cell IL-17 production, and this effect became even more pronounced after L. monocytogenes infection in mice with combined defects in both IL-12 and type I IFN receptor that develop a T helper type 17-dominated CD4(+) T-cell response. Despite increased CD4(+) T-cell IL-17 production, L. monocytogenes-specific T cells re-expanded and conferred protection against secondary challenge with virulent L. monocytogenes regardless of IL-21 deficiency, or combined defects in IL-21, IL-12, and type I IFN receptor. Together, these results demonstrate non-essential individual and combined roles for IL-21, IL-12 and type I IFNs in priming pathogen-specific CD8(+) T cells, and reveal IL-21-dependent suppression of IL-17 production by CD4(+) T cells during in vivo infection.

Repeated 0.5-Gy γ Irradiation Attenuates Experimental Autoimmune Encephalomyelitis with Up-regulation of Regulatory T Cells and Suppression of IL17 Production

We recently reported attenuation of autoimmune disease by low-dose gamma irradiation (repeated doses of 0.5 Gy) in MRL-lpr/ lpr mice. Here we studied the effect of low-dose gamma irradiation on experimental autoimmune encephalomyelitis (EAE), which is a rodent model of multiple sclerosis. SJL/J mice were immunized with myelin basic protein for the induction of EAE and were exposed to 0.5 Gy gamma rays once a week for 4 weeks. Radiation suppressed incidence and disease severity scores and delayed the onset of pathological changes. Pro-inflammatory cytokines (IFN-gamma and IL6), autoantibody and CD8+ cytotoxic T cells are involved in the appearance of EAE. Radiation suppressed the increases in these cytokines and the autoantibody production and blocked the increase in the population of CD8+ cytotoxic T cells. Production of IL17 by Th17 cells and/or gammadelta T cells, which plays a crucial role in EAE, was also significantly suppressed by radiation. Furthermore, a significant increase in regulatory T cells, which are involved in suppression of autoimmune disease, was found in irradiated EAE mice. These data suggest that low-dose gamma irradiation attenuates EAE through suppression of pro-inflammatory cytokines, reduction of cytotoxic T cells and induction of regulatory T cells.

A selective phosphodiesterase 4 (PDE4) inhibitor Zl-n-91 suppresses IL-17 production by human memory Th17 cells

Th17 cells are highly proinflammatory and involved in the immunopathogenesis of severe autoimmune diseases. Selective phosphodiesterase 4 (PDE4) inhibitors, which elevate intracellular cAMP by inhibiting the hydrolysis of cAMP, have been demonstrated to be an effective anti-inflammatory agent in airway inflammatory diseases. In the present study, we assessed the effect of a selective PDE4 inhibitor Zl-n-91 on IL-17 production by PBMCs and by purified CD4 + T cells following stimulation. The results for the first time demonstrated that the addition of Zl-n-91 into cell cultures of PBMCs and purified CD4 + T cells could result in the suppression of IL-17 production at the protein and mRNA levels. Further analysis indicated that Zl-n-91 had a direct inhibitory effect on the IL-17 production by memory Th17 cells via the suppression of activation, proliferation and division of CD4 + T cells. Our data suggested that Zl-n-91 might have beneficial effects in the treatment of IL-17-related autoimmune diseases.

Interleukin‐17 as a molecular target in immune‐mediated arthritis: Immunoregulatory properties of genetically modified murine dendritic cells that secrete interleukin‐4

Our previous studies have shown that murine dendritic cells (DCs) genetically modified to express interleukin-4 (IL-4) reduce the incidence and severity of murine collagen-induced arthritis. The present studies were performed to assess the immunoregulatory mechanisms underlying this response, by assessing the effects of IL-4 DCs on cytokine production by subsets of T helper cells. Male DBA mice ages 6-8 weeks old were immunized with type II collagen. Splenic T cells obtained during the initiation phase and the end stage of arthritis were cultured with IL-4 DCs or untransduced DCs in the presence of collagen rechallenge. Interferon-gamma (IFNgamma) and IL-17 responses were measured. Antibodies to IL-4, IL-12, and IL-23, and recombinant IL-4, IL-12, and IL-23 were used to further study the regulation of T cell cytokine production by IL-4 DCs. Splenic T cells obtained during the initiation phase of arthritis produced less IL-17 when cultured in the presence of IL-4 DCs, despite their production of increased quantities of other proinflammatory cytokines (IFNgamma and tumor necrosis factor). T cell IL-17 production after collagen rechallenge was not inhibited by a lack of IL-23, since IL-4-mediated suppression of IL-17 was not reconstituted by IL-23, an otherwise potent inducer of IL-17 production by T cells. Although IL-4 DCs can produce increased quantities of IL-12 and IFNgamma, suppression of IL-17 production by IL-4 DCs was independent of both. While IL-17 production by T cells obtained during the initiation phase of arthritis was regulated by IL-4 DCs, IL-17 production by T cells obtained during end-stage arthritis was not altered. Our data suggest that IL-4 DCs exert a therapeutic effect on collagen-induced arthritis by targeting IL-17. IL-17 suppression by IL-4 DCs is robust and is not reversed by IL-23. Timing might be important in IL-17-targeted therapy, since IL-17 production by T cells obtained during end-stage arthritis did not respond to suppression by IL-4 DCs.