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* Department of Genetics, Cell and Immunbiology, Semmelweis University, Medical School, Budapest, Hungary;
Heim Pal Children’s Hospital, Budapest, Hungary;
Clinical Research Center, Thrombosis, Haemostasis and Vascular Biology Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary; and
Inflammation Biology and Immunogenomics Research Group, Hungarian Academy of Siences-Semmelweis University and
¶ Department of Rheumatology, Semmelweis University, Medical School, Budapest, Hungary
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-
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- production (p = 0.0002), whereas NO synthase inhibitors NG-monomethyl-L-arginine and nitronidazole both inhibited IFN- production (p = 0.002 and p = 0.01, respectively), suggesting the role of NO in regulating IFN- synthesis. Cytoplasmic Ca2+ concentration of unstimulated T cells was increased in the HDC-KO mice (p = 0.02), whereas T cell activation-induced 
Ca2+-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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants OTKA F 61030 and OTKA T 046468.
2 G.N. is a Bolyai research fellow.
3 Address correspondence and reprint requests to Dr. Gyorgy Nagy, Department of Rheumatology, Semmelweis University, Medical School, Budapest, Hungary. E-mail: gyorgyngy{at}gmail.com
4 Abbreviations used in this paper used in this paper: HDC, histidine decarboxylase; ROI, reactive oxygen intermediate; HDC-KO, HDC gene knockout; WT, wild type; NOC-18, (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1,2-diolate-diethylenetriamine; DAF-FM, 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate; NOS, NO synthase; nNOS, neuronal NOS; iNOS, inducible NOS; eNOS, endothelial NOS; DC, dendritic cell.
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