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J. Biol. Chem., Vol. 279, Issue 35, 36210-36218, August 27, 2004

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Role of NFAT Proteins in IL13 Gene Transcription in Mast Cells^*

Silvia Monticelli¶, Deborah C. Solymar||**, and Anjana Rao

From the Department of Pathology, Harvard Medical School, and CBR Institute for Biomedical Research, Boston, Massachusetts 02115, the Division of Biotechnologies Applied to Medical Sciences, University of Milan, 20133 Milan, Italy, and the ^||Graduate Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02115

Th2 and mast cells are participants in the asthmatic response to allergens, and both cell types produce the cytokines interleukin (IL)-4 and IL-13. IL-13 in particular is both necessary and sufficient for experimental models of asthma. The transcription factor NFAT plays a central role in cytokine transcriptional regulation in both cell types. Here, we analyze the molecular basis of IL13 gene transcription in Th2 and mast cells. We show that NFAT1 is the major NFAT protein involved in regulating IL13 transcription in mast cells. Although NFAT2 is correctly expressed and regulated in mast cells, it does not contribute to IL13 gene transcription as shown by analysis of cells lacking NFAT2 and cells expressing a constitutively active version of NFAT2. The difference between NFAT1 and NFAT2 appears to be due to a preferential synergistic interaction of NFAT1 with GATA proteins at the IL13 promoter. We suggest that mast cells lack a co-activator protein that stabilizes the binding of NFAT2 to the IL13 promoter by interacting either with NFAT2 itself or with a DNA-bound complex of NFAT2 and GATA proteins.

Received for publication, June 8, 2004

^* This work was supported by National Institutes of Health Grant AI44432 and a grant from the Sandler Program for Asthma Research (to A. R.). 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.

This article was selected as a Paper of the Week.

^¶ Recipient of a Lady Tata Memorial Trust fellowship.

^** Student in the Graduate Program in Immunology, Division of Medical Sciences, Harvard Medical School and a Predoctoral Fellow of the Ryan Foundation.

To whom correspondence should be addressed: Harvard Medical School & CBR Inst. for Biomedical Research, Warren-Alpert Bldg., Rm. 152, 200 Longwood Ave., Boston, MA 02115. Tel.: 617-278-3260; Fax: 617-278-3280; E-mail: arao{at}cbr.med.harvard.edu.

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