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J. Biol. Chem., Vol. 279, Issue 4, 2559-2567, January 23, 2004

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Functional Cooperation between Interleukin-17 and Tumor Necrosis Factor- Is Mediated by CCAAT/Enhancer-binding Protein Family Members^*

Matthew J. Ruddy, Grace C. Wong¶, Xikui K. Liu¶||, Hiroyasu Yamamoto**, Soji Kasayama**, Keith L. Kirkwood¶, and Sarah L. Gaffen¶

From the Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, the ^¶Department of Oral Biology, School of Dental Medicine, and the Department of Periodontics and Endodontics, School of Dental Medicine, University at Buffalo, State University of New York, Buffalo, New York 14214 and the ^**Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

Interleukin (IL)-17 is a recently described cytokine involved in the amplification of inflammatory responses and pathologies. A hallmark feature of IL-17 is its ability to induce expression of other cytokines and chemokines. In addition, IL-17 potently synergizes with tumor necrosis factor- (TNF) to up-regulate expression of many target genes, particularly IL-6. Despite the many observations of IL-17 signaling synergy observed to date, little is known about the molecular mechanisms that underlie this phenomenon. In the osteoblastic cell line MC-3T3, we have found that IL-17 and TNF exhibit potent synergy in mediating IL-6 secretion. Here, we show that at least part of the functional cooperation between IL-17 and TNF occurs at the level of IL-6 gene transcription. Both the NF-B and CCAAT/enhancer-binding protein (C/EBP; NF-IL6) sites in the IL-6 promoter are important for cooperative gene expression, but NF-B does not appear to be the direct target of the combined signal. Microarray analysis using the Affymetrix mouse MG-U74v2 chip identified C/EBP as another gene target of combined IL-17- and TNF-induced signaling. Because C/EBP family members are known to control IL-6, we examined whether enhanced C/EBP expression is involved in the cooperative up-regulation of IL-6 by IL-17 and TNF. Accordingly, we show that C/EBP (or the related transcription factor C/EBP) is essential for expression of IL-6. Moreover, overexpression of C/EBP (and, to a lesser extent, C/EBP) could substitute for the IL-17 signal at the level of IL-6 transcription. Thus, C/EBP family members, particularly C/EBP, appear to be important for the functional cooperation between IL-17 and TNF.

Received for publication, August 8, 2003 , and in revised form, October 15, 2003.

^* This work was supported in part by the Arthritis Foundation, National Institutes of Health Grant AI49329, and the State University of New York at Buffalo Interdisciplinary Creative Research Activities Fund (to S. L. G.). 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.

Supported in part by National Institutes of Health Training Grant AI07614 awarded to the Witebsky Center for Microbial Pathogenesis and Immunology of the State University of New York at Buffalo.

^|| Supported by National Institutes of Health Grant DE14460.

To whom correspondence should be addressed: Dept. of Oral Biology, School of Dental Medicine, SUNY, 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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