The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines.

IL-4 promotes the differentiation of naive CD4+ T cells into IL-4-producing T helper 2 (Th2) cells. Previous work provided suggestive but not conclusive evidence that the transcription factor c-Maf directed the tissue-specific expression of IL-4. It was not known whether c-Maf controlled the transcription of other Th2 cytokine genes. To elucidate the role of c-Maf in vivo, we examined cytokine production in mice lacking c-Maf (c-maf(-/-)). CD4+ T cells and NK T cells from c-maf(-/-) mice were markedly deficient in IL-4 production. However, the mice produced normal levels of IL-13 and IgE, and, when differentiated in the presence of exogenous IL-4, c-maf(-/-) T cells produced approximately normal levels of other Th2 cytokines. We conclude that c-Maf has a critical and selective function in IL-4 gene transcription in vivo.

[1]  R. Coffman,et al.  Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. , 1986, Journal of immunology.

[2]  R. Locksley,et al.  Beta 2-microglobulin-dependent NK1.1+ T cells are not essential for T helper cell 2 immune responses , 1996, The Journal of experimental medicine.

[3]  Martin R. Hodge,et al.  NF-AT-Driven Interleukin-4 Transcription Potentiated by NIP45 , 1996, Science.

[4]  K. Rajewsky,et al.  Generation and analysis of interleukin-4 deficient mice. , 1991, Science.

[5]  L. Glimcher,et al.  Transcription Factors in Lymphocyte Development— T and B Cells Get Together , 1999, Cell.

[6]  G. Zurawski,et al.  Receptors for interleukin‐13 and interleukin‐4 are complex and share a novel component that functions in signal transduction. , 1993, The EMBO journal.

[7]  D D Donaldson,et al.  Interleukin-13: central mediator of allergic asthma , 1998 .

[8]  H. Young,et al.  IL-13 production by NK cells: IL-13-producing NK and T cells are present in vivo in the absence of IFN-gamma. , 1999, Journal of immunology.

[9]  G. McKenzie,et al.  Impaired development of Th2 cells in IL-13-deficient mice. , 1998, Immunity.

[10]  O. Lantz,et al.  Increased interleukin 4 and immunoglobulin E production in transgenic mice overexpressing NK1 T cells , 1996, The Journal of experimental medicine.

[11]  Y. Yazaki,et al.  Triple synergism of human T-lymphotropic virus type 1-encoded tax, GATA-binding protein, and AP-1 is required for constitutive expression of the interleukin-5 gene in adult T-cell leukemia cells , 1997, Molecular and cellular biology.

[12]  T. Mosmann,et al.  A family of small inducible proteins secreted by leukocytes are members of a new superfamily that includes leukocyte and fibroblast-derived inflammatory agents, growth factors, and indicators of various activation processes. , 1989, Journal of immunology.

[13]  L. Glimcher,et al.  Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. , 1996, Immunity.

[14]  W. Paul,et al.  An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  T. Baumruker,et al.  Common and distinct signaling pathways mediate the induction of TNF-alpha and IL-5 in IgE plus antigen-stimulated mast cells. , 1998, Journal of immunology.

[16]  Martin Bachmann,et al.  Disruption of the murine IL-4 gene blocks Th2 cytokine responses , 1993, Nature.

[17]  D B Corry,et al.  Requirement for IL-13 independently of IL-4 in experimental asthma. , 1998, Science.

[18]  K. Bost,et al.  In vivo treatment with anti‐interleukin‐13 antibodies significantly reduces the humoral immune response against an oral immunogen in mice , 1996, Immunology.

[19]  W. Wisden,et al.  Interleukin (IL)-4–independent Induction of Immunoglobulin (Ig)E, and Perturbation of  T Cell Development in Transgenic Mice Expressing IL-13 , 1998, The Journal of experimental medicine.

[20]  R. Coffman,et al.  Early production of IL-4 and induction of Th2 responses in the lymph node originate from an MHC class I-independent CD4+NK1.1- T cell population. , 1996, Journal of immunology.

[21]  Laurie H Glimcher,et al.  The Proto-Oncogene c-maf Is Responsible for Tissue-Specific Expression of Interleukin-4 , 1996, Cell.

[22]  M. Kaplan,et al.  Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. , 1996, Immunity.

[23]  T. Wynn,et al.  IL-13 is a key regulatory cytokine for Th2 cell-mediated pulmonary granuloma formation and IgE responses induced by Schistosoma mansoni eggs. , 1999, Journal of immunology.

[24]  W. Ouyang,et al.  Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. , 1998, Immunity.

[25]  R. de Waal Malefyt,et al.  Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[26]  F. Brombacher,et al.  Differences between IL-4Rα-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses , 1998, Current Biology.

[27]  A. Ray,et al.  Transcription Factor GATA-3 Is Differentially Expressed in Murine Th1 and Th2 Cells and Controls Th2-specific Expression of the Interleukin-5 Gene* , 1997, The Journal of Biological Chemistry.

[28]  R. Coffman,et al.  Modulation of murine macrophage function by IL-13. , 1993, Journal of immunology.

[29]  K. Arai,et al.  cAMP activates the IL-5 promoter synergistically with phorbol ester through the signaling pathway involving protein kinase A in mouse thymoma line EL-4. , 1993, Journal of immunology.

[30]  W. Paul,et al.  Lymphocyte responses and cytokines , 1994, Cell.

[31]  W. Paul,et al.  CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3 , 1994, The Journal of experimental medicine.

[32]  P. Casellas,et al.  lnterleukin-13 is a new human lymphokine regulating inflammatory and immune responses , 1993, Nature.

[33]  Tiansen Li,et al.  Requirement for the c-Maf transcription factor in crystallin gene regulation and lens development. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[34]  R. de Waal Malefyt,et al.  Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[35]  R. de Waal Malefyt,et al.  An interleukin 4 (IL-4) mutant protein inhibits both IL-4 or IL-13- induced human immunoglobulin G4 (IgG4) and IgE synthesis and B cell proliferation: support for a common component shared by IL-4 and IL-13 receptors , 1993, The Journal of experimental medicine.

[36]  A. Minty,et al.  Interleukin 13 is a B cell stimulating factor , 1994, The Journal of experimental medicine.

[37]  L. Cohn,et al.  IL-4-independent induction of airway hyperresponsiveness by Th2, but not Th1, cells. , 1998, Journal of immunology.

[38]  N. Copeland,et al.  Mouse Eotaxin expression parallels eosinophil accumulation during lung allergic inflammation but it is not restricted to a Th2-type response. , 1996, Immunity.

[39]  K A Arndt,et al.  Cutting edge , 2012, Archives of dermatology.

[40]  Laurie H Glimcher,et al.  B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: Application to autoimmune disease therapy , 1995, Cell.

[41]  R. Locksley,et al.  Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism , 1990, The Journal of experimental medicine.

[42]  Richard A Flavell,et al.  The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells , 1997, Cell.

[43]  C. Figdor,et al.  Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10. , 1993, Journal of immunology.

[44]  W. Paul,et al.  IL-4 is required to generate and sustain in vivo IgE responses. , 1988, Journal of immunology.

[45]  R. Locksley,et al.  Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets , 1989, The Journal of experimental medicine.

[46]  S. Akira,et al.  Essential role of Stat6 in IL-4 signalling , 1996, Nature.

[47]  W. Paul,et al.  Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted State6 gene , 1996, Nature.

[48]  L. Glimcher,et al.  c-maf Promotes T Helper Cell Type 2 (Th2) and Attenuates Th1 Differentiation by Both Interleukin 4–dependent and –independent Mechanisms , 1998, The Journal of experimental medicine.

[49]  M. Kaplan,et al.  Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. , 1998, Journal of immunology.

[50]  P. Foster,et al.  A novel T cell-regulated mechanism modulating allergen-induced airways hyperreactivity in BALB/c mice independently of IL-4 and IL-5. , 1998, Journal of immunology.

[51]  M. Kaplan,et al.  Immunoglobulin E Production in the Absence of Interleukin-4-Secreting CD1-Dependent Cells , 1997, Science.