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Sulforaphane protects from T cell mediated autoimmune disease by inhibition of interleukin 23 and 12 in dendritic cells

ABSTRACT: Sulforaphane (SFN), an isothiocyanate, is part of an important group of naturally occurring small molecules with antiinflammatory properties. Even though the published reports are vague, most are best conceivable with an inhibition of T cell functions. We therefore analyzed the effect of SFN on T cell-mediated autoimmune disease. Feeding mice with SFN protected from severe experimental autoimmune encephalomyelitis (EAE). Disease amelioration was associated with reduced interleukin (IL)-17 and IFN-gamma expression in draining lymph nodes. In vitro, SFN treatment of T cells did not directly alter T cell cytokine secretion. In contrast, SFN treatment of dendritic cells (DC) inhibited TLR4-induced IL-12 and IL-23 production and the cytokine profile of T cells stimulated by SFN-treated DC. SFN suppressed TLR4-induced nuclear factor kappa B (NFÎºB) activity, without affecting the degradation of its inhibitor (IÎºB). Instead, SFN treatment of DC resulted in strong expression of the stress response protein heme oxygenase-1 (HO-1), which interacts with NFÎºB p65 and inhibits its activity. Consistent with these findings, HO-1 bound to p65 and subsequently inhibited the p65 promoter activity within the IL23a and IL12b promoter region. Importantly, SFN suppressed Il23a and Il12b expression in vivo and silenced Th17/Th1 responses within the CNS . Our data show that SFN improves Th17/Th1-mediated autoimmune disease by inducing HO-1 and inhibiting p65-regulated IL-23 and IL-12 expression. Treatment-control experiment with two replicates per condition

ORGANISM(S): Mus musculus

SUBMITTER: Michael Walter

PROVIDER: E-GEOD-54980 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:IL-17A is a pro-inflammatory cytokine that promotes host defense against infections and contributes to the pathogenesis of chronic inflammatory diseases. Dendritic cells (DC) are antigen-presenting cells responsible for adaptive immune responses. Here, we report that IL-17A induces intense remodeling of lipid metabolism in human monocyte-derived DC, as revealed by microarrays analysis. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. We used microarrays analysis to understand the impact of IL-17A on human monocyte-derived human dendritic cells. We found overexpression of many genes involved in lipid metabolism in IL-17A-treated dendritic cells compared to untreated dendritic cells. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. RNA was extracted from untreated in vitro-generated DC at day 0 (DC, 4 biological replicates ) or DC cultured for 12 days with IL-17A, in the absence or presence of IFN-g (DC-17 and DC-G17, 5 biological replicates)

Project description:Dendritic cells (DC) play a crucial role in initiating, shaping and controlling the immune response. They are the most important antigen presenting cells in the immune system. DC can be divided in immature and mature DC. DCs reside in an immature state in most tissues or they circulate in the blood, where they recognize and phagocytose pathogens and other antigens. Direct contact with many pathogens leads to the maturation of DCs. The property to stimulate T cells is reserved for mature DC (O`Doherty, U. 1994). This functional maturation results in an up-regulation of the surface molecule MHC class II, adhesion molecules (CD54 and CD58) and co-stimulatory receptors (CD80 and CD86) as well as decreased antigen uptake capacity (CD206). (Banchereau, J. and Steinman, R.M. 1998). Immunosuppressive drugs have revolutionized organ transplantation and improved the therapeutic management of autoimmune diseases. These drugs interfere on lymphocytes but they also act at the earliest stage of immune response. They are targeting key functions of dendritic cells (Hackstein H. and Thomson A.W., 2004 review). Sanglifehrin A (SFA) is a new immunosuppressive drug. It is a representative of a class of macrolides produced by the actinomycetes strain Streptomyces A92-308110 that bind to cyclophilin A (CypA), the binding protein of cyclosporine A (CsA). Most studies about immunosuppressive effects of SFA took place on T and B lymphocytes. Unlike CsA, the cyclophilin-SFA-complex shows no effect on the calcium-dependent protein phosphatase calcineurin (Zenke, G. 2001). Unlike CsA and FK506, SFA shows no inhibition of IL-2 expression (Zenke, G. 2001; Zhang, L.H. 2001), nor does it suppress IL-2 receptor transcription (Zhang, L.H. 2001) in T lymphocytes. It could be shown that SFA reduces the Interleukin 12 production in dendritic cells (Steinschulte, C. 2003). IL-12p70 plays an important role in the pathogenesis of inflammation and autoimmune diseases. DCs generated in the presence of SFA show reduced macropinocytosis and lectin-mediated endocytosis. In contrast, CD89 und CD32 were increased by SFA. The effect of SFA on the expression of Ag uptake receptors and Ag capture by DCs makes SFA unique among other immunophilin-binding immunosuppressive drugs (Woltman, A. 2004). Our goal is to investigate the gene expression profile of SFA treated mature human monocyte-derived dendritic cells. Comparison of SFA-stimulated versus unstimulated cells. 7 biological replicates

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Sulforaphane protects from T cell mediated autoimmune disease by inhibition of interleukin 23 and 12 in dendritic cells

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