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Vitamin D Suppresses Th17 Cytokine Production by Inducing C/EBP Homologous Protein (CHOP) Expression*

  • Seon Hee Chang
    Affiliations
    Department of Immunology and Center for Inflammation and Cancer, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77054
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  • Yeonseok Chung
    Footnotes
    Affiliations
    Department of Immunology and Center for Inflammation and Cancer, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77054
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  • Chen Dong
    Correspondence
    An Olga and Harry Wiess Distinguished University Chair in Cancer Research of the University of Texas MD Anderson Cancer Center and a Leukemia and Lymphoma Society Scholar. To whom correspondence should be addressed
    Affiliations
    Department of Immunology and Center for Inflammation and Cancer, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77054
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  • Author Footnotes
    * This work was supported, in whole or in part, by National Institutes of Health Grant 5R01AR050772-09 (to C. D.) and a Research Trust Fellowship (to C. D.).
    1 Present address: Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030.
Open AccessPublished:October 25, 2010DOI:https://doi.org/10.1074/jbc.C110.185777
      Vitamin D has been shown to have immunomodulatory function, but the molecular basis for it has not been well understood. In this study, we found that vitamin D receptor expression was induced in a CD4+ effector T cell lineage, Th17 cells, which required the transcription factors, RORα, RORγt, and STAT3. Treatment of mice with an active ligand of vitamin D receptor (VDR), 1,25-dihydroxyvitamin D3 (1,25D3), ameliorated experimental autoimmune encephalomyelitis, accompanied with reduced IL-17 and IL-17F expression. In vitro, treatment of CD4+ T cells with the physiological doses of 1,25D3 preferentially inhibited cytokine production by Th17 cells, in a VDR-dependent manner, without affecting the expression of transcription factors or surface molecules. Moreover, at these concentrations, cytokine expression was suppressed only at protein but not at mRNA levels. Stimulation of Th17 cells with 1,25D3, in a concentration-dependent manner, induced the expression of C/EBP homologous protein (CHOP), a molecule involved in endoplasmic reticulum stress and translational inhibition. In addition, overexpression of CHOP in developing Th17 cells suppressed their cytokine production. Our results suggest a novel, post-transcriptional mechanism whereby Th17 cytokines are inhibited by VDR, which may underscore future therapeutic usage of vitamin D in treatment of autoimmune diseases.

      Introduction

      Vitamin D is an essential nutrient that regulates calcium and phosphate transport and bone mineralization (
      • Holick M.F.
      ). In recent years, however, vitamin D has been found to have a much broader range of actions, including regulation of cell differentiation, proliferation, and apoptosis (

      Mora, J. R., Iwata, M., von Andrian, U. H. (2008) Nat. Rev. Immunol..

      ). The role of vitamin D in immune system is complex and diverse. The systemic or locally produced active form of vitamin D, 1,25-dihydroxyvitamin D3(1,25D3),
      The abbreviations used are: 1,25D3
      1,25-dihydroxyvitamin D3
      VDR
      vitamin D receptor
      CHOP
      C/EBP homologous protein
      C/EBP
      CCAAT/enhancer-binding protein
      EAE
      experimental autoimmune encephalomyelitis
      PMA
      phorbol 12-myristate 13-acetate
      ROR
      retinoic acid-related orphan receptor
      MOG
      myelin oligodendrocyte glycoprotein.
      can exercise its effects on several immune cells, including macrophages, dendritic cells, and T and B cells. Several reports indicated that 1,25D3 can act directly on T cells or indirectly on dendritic cells to modulate T cell function (
      • Jeffery L.E.
      • Burke F.
      • Mura M.
      • Zheng Y.
      • Qureshi O.S.
      • Hewison M.
      • Walker L.S.
      • Lammas D.A.
      • Raza K.
      • Sansom D.M.
      ,
      • Staeva-Vieira T.P.
      • Freedman L.P.
      ,
      • Mahon B.D.
      • Wittke A.
      • Weaver V.
      • Cantorna M.T.
      ,
      • Sigmundsdottir H.
      • Pan J.
      • Debes G.F.
      • Alt C.
      • Habtezion A.
      • Soler D.
      • Butcher E.C.
      ). However, the concentrations of 1,25D3 employed in many studies are often above the physiological range, bringing into question the physiological relevance of the effect of 1,25D3 on T cells. Nonetheless, modulation of CD4+ T cells by 1,25D3 is intriguing because several studies have demonstrated that 1,25D3 is capable of suppressing inflammation in vivo (
      • Gorman S.
      • Kuritzky L.A.
      • Judge M.A.
      • Dixon K.M.
      • McGlade J.P.
      • Mason R.S.
      • Finlay-Jones J.J.
      • Hart P.H.
      ,
      • Pedersen L.B.
      • Nashold F.E.
      • Spach K.M.
      • Hayes C.E.
      ,
      • Penna G.
      • Amuchastegui S.
      • Cossetti C.
      • Aquilano F.
      • Mariani R.
      • Sanvito F.
      • Doglioni C.
      • Adorini L.
      ,
      • Tang J.
      • Zhou R.
      • Luger D.
      • Zhu W.
      • Silver P.B.
      • Grajewski R.S.
      • Su S.B.
      • Chan C.C.
      • Adorini L.
      • Caspi R.R.
      ).
      Recently, a new subset of CD4+ T cells, Th17 cells, was reported to have an essential role in dampening local inflammation (
      • Dong C.
      ,
      • Weaver C.T.
      • Hatton R.D.
      • Mangan P.R.
      • Harrington L.E.
      ,
      • Zhou L.
      • Littman D.R.
      ). Th17 cells produce proinflammatory molecules, IL-17, IL-17F, and IL-22, which act on tissue resident cells to promote inflammation. TGFβ and IL-6 are critical in generation of Th17 cells by activating STAT3 and inducing the transcription factors, retinoic acid-related orphan receptor (RORγt) (
      • Ivanov I.I.
      • McKenzie B.S.
      • Zhou L.
      • Tadokoro C.E.
      • Lepelley A.
      • Lafaille J.J.
      • Cua D.J.
      • Littman D.R.
      ) and RORα (
      • Yang X.O.
      • Pappu B.P.
      • Nurieva R.
      • Akimzhanov A.
      • Kang H.S.
      • Chung Y.
      • Ma L.
      • Shah B.
      • Panopoulos A.D.
      • Schluns K.S.
      • Watowich S.S.
      • Tian Q.
      • Jetten A.M.
      • Dong C.
      ). IL-1 and IL-23 are also important cytokines to stabilize and maintain Th17 cells (
      • Chung Y.
      • Chang S.H.
      • Martinez G.J.
      • Yang X.O.
      • Nurieva R.
      • Kang H.S.
      • Ma L.
      • Watowich S.S.
      • Jetten A.M.
      • Tian Q.
      • Dong C.
      ,
      • Langrish C.L.
      • Chen Y.
      • Blumenschein W.M.
      • Mattson J.
      • Basham B.
      • Sedgwick J.D.
      • McClanahan T.
      • Kastelein R.A.
      • Cua D.J.
      ). Therefore, pathways to regulate Th17 cell development and its cytokines are relevant. Of interest, a previous report indicated that 1,25D3 is able to prevent experimental autoimmune uveitis, partially because of its suppressive effect directly on Th17 cells (
      • Tang J.
      • Zhou R.
      • Luger D.
      • Zhu W.
      • Silver P.B.
      • Grajewski R.S.
      • Su S.B.
      • Chan C.C.
      • Adorini L.
      • Caspi R.R.
      ). However, it is not known whether the effect is mediated through vitamin D receptor (VDR) and how 1,25D3 suppresses IL-17 and other Th17 cytokine production in T cells.
      In this study, we have examined the mechanism whereby 1,25D3 regulates CD4+ T cell function at physiological concentrations. We found that in response to 1,25D3, Th17 cells produced reduced levels of cytokines at the protein level, whereas their transcriptions were not affected. Moreover, 1,25D3 treatment in Th17 cells induced the expression of C/EBP homologous protein (CHOP). Overexpression of CHOP in Th17 cells suppressed their cytokine production. Our data thus suggest a post-transcriptional inhibition of Th17 cell function by VDR.

      Acknowledgments

      We thank the members of the Dong laboratory for help.

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