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J. Biol. Chem., Vol. 281, Issue 34, 24138-24148, August 25, 2006
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Identification of Common Transcriptional Regulatory Elements in Interleukin-17 Target Genes*
¶1
From the
Department of Oral Biology, School of Dental Medicine, ¶Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, and Center for Computational Research, Department of Biostatistics, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214
Interleukin (IL)-17 is the founding member of a novel family of inflammatory cytokines. Although produced by T cells, IL-17 activates genes and signals typical of innate immune mediators such as tumor necrosis factor (TNF)-
and IL-1
. Most IL-17 target genes characterized to date are cytokines or neutrophil-attractive chemokines. Our recent microarray studies identified an acute phase response gene, 24p3/lipocalin 2, as a novel IL-17-induced gene. Here we describe a detailed analysis of the 24p3 promoter. We find that, unlike cytokine or chemokine gene target genes, 24p3 is regulated primarily at the level of transcription rather than mRNA stability and that synergy between IL-17 and TNF occurs at the level of the 24p3 promoter. Two key transcription factor binding sites (TFBS) were identified, corresponding to NF-
B and CCAAT/enhancer-binding protein (C/EBP). Deletion of either site eliminated 24p3 promoter activity in response to IL-17. These findings were strikingly similar to the IL-6 promoter, where IL-17-mediated regulation of both NF-B and C/EBP is essential. To determine whether joint use of NF-B and C/EBP is common to all IL-17 target genes, we performed a computational analysis on 18 well documented IL-17 target promoters to assess statistical enrichment of specific TFBSs. Indeed, NF-B and C/EBP sites were over-represented in these genes, as were AP1 and OCT1 sites. Moreover, these promoters fell into three definable subcategories based on TFBS location and usage. Analysis of IL-17 target gene regulation is key for understanding this important host-defense molecule and also contributes to an understanding of upstream signaling mechanisms used by IL-17, either alone or in concert with TNF.
Received for publication, May 12, 2006
* 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.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2.
1 Supported by the National Institutes of Health Grant AR050458 and the Arthritis Foundation. To whom correspondence should be addressed: 36 Foster Hall, 3435 Main St., Buffalo, NY 14214. Tel.: 716-829-2786; Fax: 716-829-3942; E-mail: sgaffen{at}buffalo.edu.
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