title: The Active Form of Vitamin D Transcriptionally Represses Smad7 Signaling and Activates Extracellular Signal-regulated Kinase (ERK) to Inhibit the Differentiation of a Inflammatory T Helper Cell Subset and Suppress Experimental Autoimmune Encephalomyelitis.
abstract: The ability of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), 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)2D3 suppression of EAE correlates with the Smad7 expression in the spleen and lymph nodes. Furthermore, Smad7 expression also correlates well with IL17 and IFNγ 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)2D3. The above canonical and non-canonical pathways in part address the ability of 1,25(OH)2D3-VDR to inhibit EAE.
authors: From the Department of Protein Science and Molecular Biology, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Sector 39 A, Chandigarh 160036, India.
authors: Ravikanth
authors: R
authors: Nanduri
authors: From the Department of Protein Science and Molecular Biology, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Sector 39 A, Chandigarh 160036, India.
authors: Sahil
authors: S
authors: Mahajan
authors: From the Department of Protein Science and Molecular Biology, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Sector 39 A, Chandigarh 160036, India.
authors: Ella
authors: E
authors: Bhagyaraj
authors: From the Department of Protein Science and Molecular Biology, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Sector 39 A, Chandigarh 160036, India.
authors: Kanupriya
authors: K
authors: Sethi
authors: From the Department of Protein Science and Molecular Biology, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Sector 39 A, Chandigarh 160036, India.
authors: Rashi
authors: R
authors: Kalra
authors: From the Department of Protein Science and Molecular Biology, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Sector 39 A, Chandigarh 160036, India.
authors: Vemika
authors: V
authors: Chandra
authors: From the Department of Protein Science and Molecular Biology, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Sector 39 A, Chandigarh 160036, India pawan@imtech.res.in.
authors: Pawan
authors: P
authors: Gupta
mesh_terms: D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007371:Interferon-gamma / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D020218:Response Elements; D051906:Smad7 Protein / Q000037:antagonists & inhibitors* / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*; D058504:Th17 Cells; D014158:Transcription, Genetic; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Autoimmune Disease; EAE; ERK; Gene Repression; Nuclear Receptor; Phosphorylation; Smad7; T Helper Cells; Transcription Target Gene; VDR