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J. Biol. Chem., Vol. 279, Issue 33, 34578-34588, August 13, 2004

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Nuclear Factor of Activated T Cells Regulates Transcription of the Surfactant Protein D Gene (Sftpd) via Direct Interaction with Thyroid Transcription Factor-1 in Lung Epithelial Cells^*

Vrushank Davé, Tawanna Childs, and Jeffrey A. Whitsett

From the Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039

Surfactant protein D (SP-D) plays critical roles in host defense, surfactant homeostasis, and pulmonary immunomodulation. Here, we identify a role of nuclear factor of activated T cells (NFATs) in regulation of murine SP-D gene (Sftpd) transcription. An NFAT-dependent enhancer modulated by NFATs or calcineurin and sensitive to cyclosporin was identified in the Sftpd promoter. Ionomycin and phorbol 12-myristate 13-acetate further increased the activity of this enhancer, whereas VIVIT, a potent NFAT inhibitor peptide, selectively interfered with the calcineurin-NFAT interaction and abolished enhancer function. Gel supershift and DNase I protection assays identified DNA elements that bind NFAT in the Sftpd promoter. Calcineurin and NFATc3 proteins were detected in the embryonic and adult mouse lung epithelium, and the mRNA expression profiles of the NFATs were similar in immortalized mouse lung epithelial cells and alveolar epithelial type II cells. NFATc3 and TTF-1 activated the Sftpd promoter, synergized transcription, co-immunoprecipitated from mouse lung epithelial cells, and physically interacted in vitro. Components of the calcineurin/NFAT pathway were identified in respiratory epithelial cells of the lung that potentially augment rapid assembly of a multiprotein transcription complex on Sftpd promoter inducing SP-D expression.

Received for publication, April 19, 2004 , and in revised form, May 21, 2004.

^* This work was supported by American Lung Association Grant RG-155-N (to V. D.) and NHLBI, National Institutes of Health, Grant HL 63329 (to J. A. W.). 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.

To whom correspondence should be addressed: Division of Pulmonary Biology, 4403, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Tel.: 513-636-8410 (office) and 513-636-3323 (laboratory); Fax: 513-636-7868; E-mail: davev0{at}cchmc.org.

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