Human IL-17F ELISA Development Kit

Background: Transcriptional regulation of Smads that modulate T helper (Th) cell differentiation is not well understood. Results: Active form of vitamin D (1,25(OH)(2)D-3) leads to VDR-RXR-Smad3-HDAC2 repressive complex on VDRE-Smad7 promoter. 1,25(OH)(2)D-3 activates ERK. Conclusion: 1,25(OH)(2)D-3-VDR represses Smad7 and activates ERK leading to inhibition of inflammatory T cells and EAE. Significance: TGF Smad and non-Smad MAPK are involved in 1,25(OH)(2)D-3-VDR mediated inhibition of EAE. The ability of the active form of vitamin D, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), to transcriptionally modulate Smads to inhibit Th17 differentiation and experimental autoimmune encephalomyelitis (EAE) has not been adequately studied. This study reports modulation of Smad signaling by the specific binding of the VDR along with its heterodimeric partner RXR to the negative vitamin D response element on the promoter of Smad7, which leads to Smad7 gene repression. The vitamin D receptor-mediated increase in Smad3 expression partially explains the IL10 augmentation seen in Th17 cells. Furthermore, the VDR axis also modulates non-Smad signaling by activating ERK during differentiation of Th17 cells, which inhibits the Th17-specific genes il17a, il17f, il22, and il23r. In vivo EAE experiments revealed that, 1,25(OH)(2)D-3 suppression of EAE correlates with the Smad7 expression in the spleen and lymph nodes. Furthermore, Smad7 expression also correlates well with IL17 and IFN expression in CNS infiltered inflammatory T cells. We also observed similar gene repression of Smad7 in in vitro differentiated Th1 cells when cultured in presence of 1,25(OH)(2)D-3. The above canonical and non-canonical pathways in part address the ability of 1,25(OH)(2)D-3-VDR to inhibit EAE.

We recently characterized Winnie mice carrying a missense mutation in Muc2, leading to severe endoplasmic reticulum stress in intestinal goblet cells and spontaneous colitis. In this study, we characterized the immune responses due to this intestinal epithelial dysfunction. In Winnie, there was a fourfold increase in activated dendritic cells (DCs; CD11c(+) major histocompatibility complex (MHC) class IIhi) in the colonic lamina propria accompanied by decreased colonic secretion of an inhibitor of DC activation, thymic stromal lymphopoietin (TSLP). Winnie also displayed a significant increase in mRNA expression of the mucosal T(H)17 signature genes Il17a, IL17f, Tgfb, and Ccr6, particularly in the distal colon. Winnie mesenteric lymph node leukocytes secreted multiple T(H)1, T(H)2, and T(H)17 cytokines on activation, with a large increase in interleukin-17A (IL-17A) progressively with age. A major source of mucosal IL-17A in Winnie was CD4(+) T lymphocytes. Loss of T and B lymphocytes in Rag1(-/-) x Winnie (RaW) crosses did not prevent spontaneous inflammation but did prevent progression with age in the colon but not the cecum. Adoptive transfer of naive T cells into RaW mice caused more rapid and severe colitis than in Rag1(-/-), indicating that the epithT(H)elial defect results in an intestinal microenvironment conducive to T-cell activation. Thus, the Winnie primary epithelial defect results in complex multicytokine-mediated colitis involving both innate and adaptive immune components with a prominent IL-23/T(H)17 response, similar to that of human ulcerative colitis.