Vitamin D3: a transcriptional modulator of the interferon‐γ gene

1α,25‐Dihydroxyvitamin D3 [1225‐(OH)2D3] exerts several effects on the immune system, by regulating lymphocyte proliferation, differentiation of monocytes and secretion of cytokines as IL‐2, granulocyte‐macrophage colony‐stimulating factor and IFN‐γ in T cells. Here, we analyze the effect of 1,25‐(OH)2D3 on IFN‐γ gene transcription. Transient transfection assays in Jurkat T cells indicate that activation of the IFN‐γ promoter is down‐regulated by 1,25‐(OH)2D3. This effect is enhanced by retinoid X receptor (RXR), and a functional vitamin D3 receptor (VDR) DNA‐binding domain in necessary for repression. We delineated two important promoter regions mainly involved in this modulation. The first of these is situated at the level of a promoter‐silencer previously characterized and binds the heterodimer VDR‐RXR in electrophoretic mobility shift assay. Residual negative regulation was also detected at the level of the promoter fragment – 108 to + 64 bp from the transcription start site and, surprisingly, the activity of the IFN‐γ enhancer from – 108 to – 36 bp in the context of a heterologous promoter was not affected by 1,25‐(OH)2D3. Moreover, binding activity for VDR‐RXR has been detected in the IFN‐γ minimal promoter, suggesting a possible mechanism of interference with transcription initiation/progression. The overall data indicate that direct modulation of the IFN‐γ promoter activity is one of the possible mechanisms involved in the repressive effect of 1,25‐(OH)2D3 on IFN‐γ gene expression.

[1]  K. Matsushima,et al.  Novel mechanism of glucocorticoid-mediated gene repression. Nuclear factor-kappa B is target for glucocorticoid-mediated interleukin 8 gene repression. , 1994, The Journal of biological chemistry.

[2]  A. Tobler,et al.  1 alpha,25-Dihydroxyvitamin D3 inhibits gamma-interferon synthesis by normal human peripheral blood lymphocytes. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[3]  S. Kliewer,et al.  Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor , 1990, Cell.

[4]  M. Jensen,et al.  Interferon γ- and interleukin-4-secreting cells in multiple sclerosis , 1993, Journal of Neuroimmunology.

[5]  G. Saggese,et al.  Calcitriol inhibits the PHA-induced production of IL-2 and IFN-γ and the proliferation of human peripheral blood leukocytes while enhancing the surface expression of HLA class II molecules , 1989, Journal of endocrinological investigation.

[6]  H. Young,et al.  Interferon-γ: Producer cells, activation stimuli, and molecular genetic regulation , 1990 .

[7]  A. Sica,et al.  Negative Transcriptional Regulation of the Interferon-γ Promoter by Glucocorticoids and Dominant Negative Mutants of c-Jun (*) , 1995, The Journal of Biological Chemistry.

[8]  V K Chatterjee,et al.  Negative regulation of the thyroid-stimulating hormone alpha gene by thyroid hormone: receptor interaction adjacent to the TATA box. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[9]  S. Kliewer,et al.  Retinoic acid is a negative regulator of AP-1-responsive genes. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[10]  R. W. Baldwin.  The immunobiology ofvitamin D William F.C. Rigby. , 1988, Immunology today.

[11]  W. M. Weaver,et al.  The Proximal Regulatory Element of the Interferon-γ Promoter Mediates Selective Expression in T Cells* , 1996, The Journal of Biological Chemistry.

[12]  H. DeLuca,et al.  1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Karin,et al.  Transcriptional interference between c-Jun and the glucocorticoid receptor: Mutual inhibition of DNA binding due to direct protein-protein interaction , 1990, Cell.

[14]  H. Koeffler,et al.  Synthesis in vitro of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 by interferon-gamma-stimulated normal human bone marrow and alveolar macrophages. , 1987, The Journal of biological chemistry.

[15]  K. Krause,et al.  The effects of 1,25-dihydroxyvitamin D3 on human T lymphocyte activation and proliferation: a cell cycle analysis. , 1985, Journal of immunology.

[16]  A. Ray,et al.  On the mechanism for efficient repression of the interleukin-6 promoter by glucocorticoids: enhancer, TATA box, and RNA start site (Inr motif) occlusion , 1990, Molecular and cellular biology.

[17]  J. Cidlowski,et al.  Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors , 1995, Molecular and cellular biology.

[18]  J. Lemire.  Immunomodulatory actions of 1,25-Dihydroxyvitamin D3 , 1995, The Journal of Steroid Biochemistry and Molecular Biology.

[19]  C. Glass,et al.  RXRβ: A coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements , 1991, Cell.

[20]  J. Ye,et al.  The nuclear factor YY1 suppresses the human gamma interferon promoter through two mechanisms: inhibition of AP1 binding and activation of a silencer element , 1996, Molecular and cellular biology.

[21]  R. Hirsch,et al.  EXACERBATIONS OF MULTIPLE SCLEROSIS IN PATIENTS TREATED WITH GAMMA INTERFERON , 1987, The Lancet.

[22]  R. Bouillon,et al.  Structure-function relationships in the vitamin D endocrine system. , 1995, Endocrine reviews.

[23]  I. Screpanti,et al.  Glucocorticoid receptor-mediated suppression of the interleukin 2 gene expression through impairment of the cooperativity between nuclear factor of activated T cells and AP-1 enhancer elements , 1992, The Journal of experimental medicine.

[24]  Naofumi MukaidaSg,et al.  Novel Mechanism of Glucocorticoid-mediated Gene Repression , 1994 .

[25]  M. Cantorna,et al.  Vitamin A deficiency results in a priming environment conducive for Th1 cell development , 1995, European journal of immunology.

[26]  M. Fanger,et al.  Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA. , 1987, The Journal of clinical investigation.

[27]  A. Sica,et al.  Retinoic Acid-induced Transcriptional Modulation of the Human Interferon-γ Promoter* , 1996, The Journal of Biological Chemistry.

[28]  M. Cuzner,et al.  Cytokine mRNA expression in inflammatory multiple sclerosis lesions: detection by non-radioactive in situ hybridization. , 1993, Cytokine.

[29]  P. Albert,et al.  Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. , 1995, Journal of immunology.

[30]  I. Screpanti,et al.  Positive and negative regulation of the composite octamer motif of the interleukin 2 enhancer by AP-1, Oct-2, and retinoic acid receptor , 1994, The Journal of experimental medicine.

[31]  L. Freedman,et al.  Ligand modulates the conversion of DNA-bound vitamin D3 receptor (VDR) homodimers into VDR-retinoid X receptor heterodimers , 1994, Molecular and cellular biology.

[32]  W. Rigby.  The immunobiology of vitamin D. , 1988, Immunology today.

[33]  Thorsten Heinzel,et al.  A CBP Integrator Complex Mediates Transcriptional Activation and AP-1 Inhibition by Nuclear Receptors , 1996, Cell.

[34]  M. Galligan,et al.  Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene , 1993, Molecular and cellular biology.

[35]  J. Shine,et al.  1,25-dihydroxyvitamin D-responsive element and glucocorticoid repression in the osteocalcin gene. , 1989, Science.

[36]  H. Samuels,et al.  The NF-kappa B and Sp1 motifs of the human immunodeficiency virus type 1 long terminal repeat function as novel thyroid hormone response elements , 1993, Molecular and cellular biology.

[37]  S. Manolagas,et al.  Down-regulation of NF-kappa B protein levels in activated human lymphocytes by 1,25-dihydroxyvitamin D3. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[38]  W. M. Weaver,et al.  Two essential regulatory elements in the human interferon gamma promoter confer activation specific expression in T cells , 1993, The Journal of experimental medicine.

[39]  K. Ozono,et al.  The vitamin D-responsive element in the human osteocalcin gene. Association with a nuclear proto-oncogene enhancer. , 1990, The Journal of biological chemistry.

[40]  L. Freedman,et al.  Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor , 1995, Molecular and cellular biology.