Nitric oxide mediates T cell cytokine production and signal transduction in histidine decarboxylase knockout mice.
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.
Koncz
Agnes
A
Department of Genetics, Cell and Immunbiology, Semmelweis University, Medical School, Budapest, Hungary.
Pasztoi
Maria
M
Mazan
Mercedesz
M
Fazakas
Ferenc
F
Buzas
Edit
E
Falus
Andras
A
Nagy
Gyorgy
G
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006632:Histamine / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D017442:Histamine Agonists / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000276:immunology; D018417:Th1 Cells / Q000201:enzymology* / Q000276:immunology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D017442:Histamine Agonists; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D006632:Histamine; D007371:Interferon-gamma; D006640:Histidine Decarboxylase