Nitric oxide increased interleukin‐4 expression in T lymphocytes

Nitric oxide (NO) is a regulator of many biological functions including T helper 1 (Th1)/T helper 2 cells balance. It has been demonstrated that NO inhibits the secretion of interleukin‐2 (IL‐2) and interferon‐γ on Th1 cells. Here we showed that, in addition to the suppression of IL‐2 production, NO‐generating agents sodium nitroprusside (SNP) and S‐nitroso‐N‐acetylpenicillamine (SNAP) increased the secretion of IL‐4 both in Th2 clones and EL4 T cells. The additive effect was dependent on the dose of SNP and SNAP. Augmentation of IL‐4 production was detected with 1 μM SNP, and up to threefold increase in IL‐4 secretion could be observed with higher concentrations of SNP/SNAP. NO also weakly increased the activation of IL‐4 promoter. In contrast, NO markedly inhibited the induction of IL‐2 promoter, which could account for most of the reduction in IL‐2 production. Analysis of the transcriptional elements on IL‐2 and IL‐4 promoters revealed a selective inactivation of NF‐κB and NF‐AT. It is suggested that despite the complex feedback network regulating NO production, the enhanced IL‐4 expression would lead to the expansion of Th2 cells once NO is generated.

[1]  M. Modolell,et al.  Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow‐derived macrophages by TH 1 and TH 2 cytokines , 1995, European journal of immunology.

[2]  B. Luckow,et al.  CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements , 1987, Nucleic Acids Res..

[3]  K. Murphy,et al.  Role of cytokines in determining T-lymphocyte function. , 1994, Current opinion in immunology.

[4]  W. Greene,et al.  The 65-kDa subunit of human NF-kappa B functions as a potent transcriptional activator and a target for v-Rel-mediated repression. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[5]  D. Chou,et al.  Flexibility of the T cell receptor repertoire , 1994, European journal of immunology.

[6]  D. Levine,et al.  Activation of human peripheral blood mononuclear cells by nitric oxide-generating compounds. , 1993, Journal of immunology.

[7]  A. Lichtman,et al.  Regulation of NF-kappa B activation in T helper 1 and T helper 2 cells. , 1996, Journal of immunology.

[8]  B. Franza,et al.  RelA/p65 is a molecular target for the immunosuppressive action of protein kinase A. , 1995, The EMBO journal.

[9]  W. Paul,et al.  Heterogeneity of helper/inducer T lymphocytes. I. Lymphokine production and lymphokine responsiveness , 1987, The Journal of experimental medicine.

[10]  P. Libby,et al.  Induction and Stabilization of IκBα by Nitric Oxide Mediates Inhibition of NF-κB (*) , 1995, The Journal of Biological Chemistry.

[11]  I. Charles,et al.  Altered immune responses in mice lacking inducible nitric oxide synthase , 1995, Nature.

[12]  J. Williamson,et al.  Modulation of in vivo alloreactivity by inhibition of inducible nitric oxide synthase , 1995, The Journal of experimental medicine.

[13]  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.

[14]  B. Wold,et al.  Interleukin-2 transcription is regulated in vivo at the level of coordinated binding of both constitutive and regulated factors , 1994, Molecular and cellular biology.

[15]  R. Locksley,et al.  Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection , 1994, The Journal of experimental medicine.

[16]  A. Taylor-Robinson,et al.  Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells , 1994, European journal of immunology.

[17]  E. Rothenberg,et al.  Regulatory anatomy of the murine interleukin-2 gene. , 1990, Nucleic acids research.

[18]  C. Nathan,et al.  Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase , 1995, Cell.

[19]  R. Coffman,et al.  A minority subpopulation of CD4+ T cells directs the development of naive CD4+ T cells into IL-4-secreting cells. , 1994, Journal of immunology.

[20]  M. Marletta,et al.  Nitric oxide synthase: Aspects concerning structure and catalysis , 1994, Cell.

[21]  C. Janeway,et al.  Growth of a cloned helper T cell line induced by a monoclonal antibody specific for the antigen receptor: interleukin 1 is required for the expression of receptors for interleukin 2. , 1984, Journal of immunology.

[22]  A. Rao,et al.  Transcriptional regulation of the IL-2 gene. , 1995, Current opinion in immunology.

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

[24]  D. Chen,et al.  Interleukin 2 transcription factors as molecular targets of cAMP inhibition: delayed inhibition kinetics and combinatorial transcription roles , 1994, The Journal of experimental medicine.

[25]  L. Glimcher,et al.  Transcription of the interleukin 4 gene is regulated by multiple promoter elements , 1993, The Journal of experimental medicine.

[26]  J. W. Rooney,et al.  Novel NFAT sites that mediate activation of the interleukin-2 promoter in response to T-cell receptor stimulation , 1995, Molecular and cellular biology.

[27]  G. Enikolopov,et al.  Amplification of calcium-induced gene transcription by nitric oxide in neuronal cells , 1993, Nature.

[28]  A Radbruch,et al.  Induction of interleukin 4 (IL-4) expression in T helper (Th) cells is not dependent on IL-4 from non-Th cells , 1994, The Journal of experimental medicine.

[29]  P. Barnes,et al.  Nitric oxide and asthmatic inflammation. , 1995, Immunology today.

[30]  J. Stamler,et al.  Redox signaling: Nitrosylation and related target interactions of nitric oxide , 1994, Cell.

[31]  J. W. Rooney,et al.  Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene. , 1995, Immunity.

[32]  H. Tony,et al.  Major histocompatibility complex-restricted, polyclonal B cell responses resulting from helper T cell recognition of antiimmunoglobulin presented by small B lymphocytes , 1985, The Journal of experimental medicine.

[33]  M. Seldin,et al.  The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L- arginine , 1994, The Journal of experimental medicine.