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Histidine Decarboxylase Knockout Mice Production and Signal Nitric Oxide Mediates T Cell Cytokine Production and Signal Transduction in Histidine Decarboxylase Knockout Mice This information is current as Agnes Koncz, Maria Pasztoi, Mercedesz Mazan, Ferenc of October 1, 2021. Fazakas, Edit Buzas, Andras Falus and Gyorgy Nagy J Immunol 2007; 179:6613-6619; ; doi: 10.4049/jimmunol.179.10.6613 http://www.jimmunol.org/content/179/10/6613 Downloaded from References This article cites 41 articles, 8 of which you can access for free at: http://www.jimmunol.org/content/179/10/6613.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Nitric Oxide Mediates T Cell Cytokine Production and Signal Transduction in Histidine Decarboxylase Knockout Mice1 Agnes Koncz,*† Maria Pasztoi,* Mercedesz Mazan,* Ferenc Fazakas,‡ Edit Buzas,* Andras Falus,*§ and Gyorgy Nagy2,3*¶ 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 (0.0009 ؍ respectively) were associated with a markedly increased (2.5-fold, p ,0.001 ؍ protein levels of splenocytes (p < 0.001; p NO production, compared with WT animals. Furthermore, histamine treatment decreased the NO production of splenocytes from Downloaded from (respectively). NO precursor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl ,0.0004 ؍ p ;0.001 ؍ both WT and HDC-KO mice (p -whereas NO synthase inhibitors NG ,(0.0002 ؍ amino] diazen-1-ium-1,2-diolate-diethylenetriamine elicited IFN-␥ production (p respectively), suggesting the ,0.01 ؍ and p 0.002 ؍ monomethyl-L-arginine and nitronidazole both inhibited IFN-␥ production (p role of NO in regulating IFN-␥ synthesis. Cytoplasmic Ca2؉ concentration of unstimulated T cells was increased in the HDC-KO whereas T cell activation-induced ␦ Ca2؉-signal was similar in both HDC-KO and WT animals. Our present data ,(0.02 ؍ mice (p indicate that, in addition to its direct effects on T lymphocyte function, histamine regulates cytokine production and T cell signal http://www.jimmunol.org/ transduction through regulating NO production. The Journal of Immunology, 2007, 179: 6613–6619. istamine, released from effector cells (mast cells and ba- est activity of HDC and histamine content were detected in mast sophils) during inflammatory reactions, can influence cells and basophils, the expression of HDC and histamine was H the immune responses (1). Mast cells, the primary ef- observed in nearly all of the proliferative tissues studied, suggest- fectors of immediate-type allergic reactions, reside in peripheral ing a possible further biological relevance of histamine (3). In tissue that directly interface with the external environment. addition to its effect on effector cells, histamine also presents im- Crosslinking of surface IgE by cognate Ags or direct binding of munoregulatory properties as it modulates cytokine production by microbial products or complement components to cellular recep- different cell types. Histamine exerts its effects through four types by guest on October 1, 2021 tors induce mast cells to release large amounts of inflammatory of histamine receptors (H1, H2, H3, and H4), signaling via differ- mediators, such as histamine, proteases, prostaglandins, and leu- ent signal-transduction pathways (4, 5). kotrienes (2). Histamine accounts for ϳ10% of mast cell granule Engagement of TCR leads to the activation of multiple protein 4 content. It is exclusively the histidine decarboxylase (HDC) en- tyrosine and serine kinases, resulting in the phosphorylation of zyme that generates histamine from L-histidine. Although the high- intracellular substrates. The subsequent hydrolysis of phospholip- ids and elevation of cytoplasmic Ca2ϩ ultimately leads to clonal *Department of Genetics, Cell and Immunbiology, Semmelweis University, Medical expansion of Ag-specific T cells (6). Once activated, CD4 T cells † School, Budapest, Hungary; Heim Pal Children’s Hospital, Budapest, Hungary; proliferate and differentiate into two main subsets of primary ef- ‡Clinical Research Center, Thrombosis, Haemostasis and Vascular Biology Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical and fector cells, Th1 or Th2 cells, characterized by their specific cy- Health Science Center, Debrecen, Hungary; and §Inflammation Biology and Immu- tokine expression pattern (7). Th1 cells promote cellular immunity nogenomics Research Group, Hungarian Academy of Siences-Semmelweis Univer- sity and ¶Department of Rheumatology, Semmelweis University, Medical School, and macrophage activation largely through the production of IL-2 Budapest, Hungary and IFN-␥ (8). Th2 cells, through the expression of IL-4, IL-5, and Received for publication April 18, 2007. Accepted for publication September IL-13, induce IgE production by B cells and eosinophil-mediated 13, 2007. and mast-cell-mediated immune responses, and orchestrate the de- The costs of publication of this article were defrayed in part by the payment of page fense against extracellular parasites (9). Th2 cells have a central charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. role in driving the immune response in asthma and atopic diseases 1 This work was supported by Grants OTKA F 61030 and OTKA T 046468. (10). The Th1/Th2 balance is therefore considered to be pivotal in chronic inflammatory diseases. Recently, Th17 cells have been 2 G.N. is a Bolyai research fellow. identified as cells induced by IL-6 and TGF-␤ and expanded by 3 Address correspondence and reprint requests to Dr. Gyorgy Nagy, Department of Rheumatology, Semmelweis University, Medical School, Budapest, Hungary. E-mail: IL-23 (11). Th17 cells have been strongly implicated as well in [email protected] allergic diseases (12). Histamine selectively enhances the secretion 4 Abbreviations used in this paper used in this paper: HDC, histidine decarboxylase; of Th2 cytokines, such as IL-4, IL-5, IL-10, and IL-13, and inhibits ROI, reactive oxygen intermediate; HDC-KO, HDC gene knockout; WT, wild type; the production of Th1 cytokines IL-2 and IFN-␥ (13) and mono- NOC-18, (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1,2-dio- late-diethylenetriamine; DAF-FM, 4-amino-5-methylamino-2Ј,7Ј-difluorofluorescein kine IL-12 (10, 14). The crucial role of histamine in the early diacetate; NOS, NO synthase; nNOS, neuronal NOS; iNOS, inducible NOS; eNOS, events of the pathogenesis of atopic asthma is associated with the endothelial NOS; DC, dendritic cell. increased production of Th2 and decreased production of Th1 cy- Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 tokines (10). www.jimmunol.org 6614 NO MEDIATES T CELL SIGNAL TRANSDUCTION IN HDC-KO MICE Crosslinking of the TCR has been associated with elevation of ELISPOT 2ϩ the cytosolic Ca , reactive oxygen intermediate (ROI), NO pro- Splenocytes were plated in duplicates in 96-well plates (MultisScreen; Mil- duction, and mitochondrial hyperpolarization (15). In contrast to lipore) (105 cells/plate) precoated with an anti-IFN-␥, anti-IL-10, or anti- histamine, NO selectively enhances Th1 cell proliferation (16) and IL-4 capture mAb (mouse IFN-␥, IL-10, and IL-4 Duoset; R& D Systems), represents an additional signal for the induction of T cell subset blocked in the presence of 1% FCS-containing PBS for1hat37°C, and ␮ response (17). Although there were several pharmacological ap- were stimulated with 2 g/ml Con-A (Sigma-Aldrich) for 24 h at 37°C, 5% CO2. After washing with PBS-Tween 20 ten times, the cells were incu- proaches to study the biological role of histamine in allergic and bated with biotinylated anti-IFN-␥, anti IL-10, or anti IL-4 detection mAb autoimmune diseases, its exact role in immune regulation is far (mouse IFN-␥, IL-4, and IL-10 Duoset, R&D Systems) for 2 h followed by from being uncovered. It has been shown that both histamine and 10 washes and incubation with streptavidin-HRP conjugate for 1 h, and NO can modulate the cytokine network in multiple ways, however, then, after ten further washes by the chromogenic substrate (aminoethyl carbazole, Sigma-Aldrich and H2O2) for 20 min, the plates were washed the possible role of NO in the immunoregulatory functions of his- with distilled water. The number of IFN-␥, IL-10, or IL-4 producing spot tamine is not known (18). In our present study, we investigated the forming cells was counted by ELISPOT reader (CTL). In some experi- effect of genetically induced histamine deficiency on T lymphocyte ments, ELISPOT assays were performed in the presence of NO donor cytokine expression and T cell activation, using HDC gene knock- (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2- G out (HDC-KO) and congenic wild-type (WT) mice.
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