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* Institute for Immunology and
III. Medical Clinic, University of Mainz, Germany; and
Institute of Pathology, Department of Molecular Pathology, University of Würzburg, Wurzburg, Germany
By virtue of their ability to express a plethora of biologically highly active mediators, mast cells (MC) are involved in both adaptive and innate immune responses. MC-derived Th2-type cytokines are thought to act as local amplifiers of Th2 reactions, including chronic inflammatory disorders such as allergic asthma, whereas MC-derived TNF-
is a critical initiator of antimicrobial defense. In this study, we demonstrate that the transcription factors NFATc1 and NFATc2 are part of a MC-specific signaling network that regulates the expression of TNF- and IL-13, whereas NFATc3 is dispensable. Primary murine bone marrow-derived MC from NFATc2–/– mice, activated by either ionomycin or IgE/Ag cross-link, display a strong reduction in the production of these cytokines, compared with bone marrow-derived MC from wild-type mice. Detailed analyses of TNF- and IL-13 expression using small interfering RNA-mediated knockdown reveals that both NFATc2 and NFATc1 are able to drive the expression of these cytokines, whereas neither degranulation nor the expression of IL-6 depends on NFAT activity. These results support the view that high NFAT activity is necessary for TNF- and IL-13 promoter induction in MC, irrespective of whether NFATc2 or NFATc1 or a combination of both is present.
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 Deutsche Forschungsgemeinschaft Grant SCHM10014/4-2 (to E.S. and M.S.) and Sonderforschungsbereich Grant 548A10 (to M.S.).
2 Address correspondence and reprint requests to Dr. Michael Stassen, Institute for Immunology, Johannes Gutenberg University, Hochhaus am Augustusplatz, D-55131 Mainz, Germany. E-mail address: stassenm{at}uni-mainz.de
3 Abbreviations used in this paper: MC, mast cell; SCF, stem cell factor; CsA, cyclosporin A; BMMC, bone marrow-derived MC; qRT-PCR, quantitative RT-PCR; ChIP, chromatin immunoprecipitation; siRNA, small interfering RNA.
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