Nitric oxide mediates T cell cytokine production and signal transduction in histidine decarboxylase knockout mice

J Immunol. 2007 Nov 15;179(10):6613-9. doi: 10.4049/jimmunol.179.10.6613.


Histamine is a key regulator of the immune system. Several lines of evidence suggest the role of histamine in T cell activation and accelerated Th1 immune response is a hallmark of histidine decarboxylase knockout (HDC-KO) mice, with a complete lack of endogenously produced histamine. According to our previous work, T lymphocytes produce NO upon activation, and NO is necessary for effective T cell activation. To study the role of histamine in T cell activation, we investigated cytokine production and T cell signal transduction in HDC-KO and wild-type (WT) mice. In the absence of histamine, an elevated IFN-gamma mRNA and protein levels of splenocytes (p < 0.001; p = 0.001, respectively) were associated with a markedly increased (2.5-fold, p = 0.0009) NO production, compared with WT animals. Furthermore, histamine treatment decreased the NO production of splenocytes from both WT and HDC-KO mice (p = 0.001; p = 0.0004, respectively). NO precursor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1,2-diolate-diethylenetriamine elicited IFN-gamma production (p = 0.0002), whereas NO synthase inhibitors N(G)-monomethyl-L-arginine and nitronidazole both inhibited IFN-gamma production (p = 0.002 and p = 0.01, respectively), suggesting the role of NO in regulating IFN-gamma synthesis. Cytoplasmic Ca(2+) concentration of unstimulated T cells was increased in the HDC-KO mice (p = 0.02), whereas T cell activation-induced delta Ca(2+)-signal was similar in both HDC-KO and WT animals. Our present data indicate that, in addition to its direct effects on T lymphocyte function, histamine regulates cytokine production and T cell signal transduction through regulating NO production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Enzyme Inhibitors / pharmacology
  • Histamine / immunology
  • Histamine / metabolism*
  • Histamine / pharmacology
  • Histamine Agonists / immunology
  • Histamine Agonists / metabolism
  • Histamine Agonists / pharmacology
  • Histidine Decarboxylase / genetics
  • Histidine Decarboxylase / immunology
  • Histidine Decarboxylase / metabolism*
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide / immunology
  • Th1 Cells / enzymology*
  • Th1 Cells / immunology
  • omega-N-Methylarginine / pharmacology


  • Enzyme Inhibitors
  • Histamine Agonists
  • omega-N-Methylarginine
  • Nitric Oxide
  • Histamine
  • Interferon-gamma
  • Histidine Decarboxylase