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A Central Role for Transcription Factor C/EBP-β in Regulating CD1d Gene Expression in Human Keratinocytes¹

Hashmat Sikder^*, Yuming Zhao^*, Anna Balato^*, Andre Chapoval, Rita Fishelevich^*, Padmaja Gade, Ishwar S. Singh, Dhananjaya V. Kalvakolanu^¶, Peter F. Johnson^* and Anthony A. Gaspari^2,*,

^* Department of Dermatology, Department of Otolaryngology-Head and Neck Surgery, Department of Microbiology and Immunology, and Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; and ^¶ National Cancer Institute, Frederick, MD 21702

CD1d is a nonclassical Ag-presenting molecule that presents glycolipid Ags to NKT cells that are involved in immune defense and tumor rejection. It also plays a role in immunoregulatory functions in the epidermis. The mechanisms controlling the expression of CD1d are not well understood. Therefore, we cloned the CD1d gene promoter and characterized its activities in primary human keratinocytes and other cell lines of epithelial origin. We found that a CCAAT box in the CD1d promoter is required for its expression in keratinocytes. We show here that transcription factor C/EBP-β binds to the CCAAT box in the CD1d promoter in vitro and in vivo. Consistent with these observations, deletion of the gene encoding for C/EBP-β caused a loss of CD1d expression. The in vivo regulation of CD1d has significant implications for the pathologic mechanisms of certain immunologic skin diseases in which NKT cells play a role, such as allergic contact dermatitis and psoriasis. Together, these data show a central role for C/EBP-β in regulating CD1d transcription.

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 Grant R0-1-AR46108-05 (to A.A.G.), CA78282 and CA105005 (to D.V.K.), and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (to P.F.J.).

² Address correspondence and reprint requests to Dr. Peter F. Johnson and Dr. Anthony A. Gaspari, Department of Dermatology, School of Medicine, University of Maryland Baltimore, 405 West Redwood Street, 6th floor, Baltimore, MD 21201. E-mail address: agasp001{at}umaryland.edu

³ Abbreviations used in this paper: KC, keratinocyte; ChIP, chromatin immunoprecipitation; qPCR, quantitative PCR; siRNA, small interfering RNA; ACD, allergic contact dermatitis; RARE, retinoid acid response element; iNKT, invariant NKT; qRT-PCR, quantitative real-time RT-PCR.