HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 279/4/2559    most recent M308809200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ruddy, M. J. Articles by Gaffen, S. L. Search for Related Content PubMed PubMed Citation Articles by Ruddy, M. J. Articles by Gaffen, S. L. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S.L. Gaffen and G. Hajishengallis A New Inflammatory Cytokine on the Block: Re-thinking Periodontal Disease and the Th1/Th2 Paradigm in the Context of Th17 Cells and IL-17 J. Dent. Res., September 1, 2008; 87(9): 817 - 828. [Abstract] [Full Text] [PDF]

				J. J. Yu, M. J. Ruddy, H. R. Conti, K. Boonanantanasarn, and S. L. Gaffen The Interleukin-17 Receptor Plays a Gender-Dependent Role in Host Protection against Porphyromonas gingivalis-Induced Periodontal Bone Loss Infect. Immun., September 1, 2008; 76(9): 4206 - 4213. [Abstract] [Full Text] [PDF]

				X. O. Yang, S. H. Chang, H. Park, R. Nurieva, B. Shah, L. Acero, Y.-H. Wang, K. S. Schluns, R. R. Broaddus, Z. Zhu, et al. Regulation of inflammatory responses by IL-17F J. Exp. Med., May 12, 2008; 205(5): 1063 - 1075. [Abstract] [Full Text] [PDF]

				D. N. Patel, C. A. King, S. R. Bailey, J. W. Holt, K. Venkatachalam, A. Agrawal, A. J. Valente, and B. Chandrasekar Interleukin-17 Stimulates C-reactive Protein Expression in Hepatocytes and Smooth Muscle Cells via p38 MAPK and ERK1/2-dependent NF-{kappa}B and C/EBPbeta Activation J. Biol. Chem., September 14, 2007; 282(37): 27229 - 27238. [Abstract] [Full Text] [PDF]

				A. Maitra, F. Shen, W. Hanel, K. Mossman, J. Tocker, D. Swart, and S. L. Gaffen Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression PNAS, May 1, 2007; 104(18): 7506 - 7511. [Abstract] [Full Text] [PDF]

				J. J. Yu, M. J. Ruddy, G. C. Wong, C. Sfintescu, P. J. Baker, J. B. Smith, R. T. Evans, and S. L. Gaffen An essential role for IL-17 in preventing pathogen-initiated bone destruction: recruitment of neutrophils to inflamed bone requires IL-17 receptor-dependent signals Blood, May 1, 2007; 109(9): 3794 - 3802. [Abstract] [Full Text] [PDF]

				S. H. Chang, H. Park, and C. Dong Act1 Adaptor Protein Is an Immediate and Essential Signaling Component of Interleukin-17 Receptor J. Biol. Chem., November 24, 2006; 281(47): 35603 - 35607. [Abstract] [Full Text] [PDF]

				F. Shen, Z. Hu, J. Goswami, and S. L. Gaffen Identification of Common Transcriptional Regulatory Elements in Interleukin-17 Target Genes J. Biol. Chem., August 25, 2006; 281(34): 24138 - 24148. [Abstract] [Full Text] [PDF]

				C. Sutton, C. Brereton, B. Keogh, K. H.G. Mills, and E. C. Lavelle A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis J. Exp. Med., July 10, 2006; 203(7): 1685 - 1691. [Abstract] [Full Text] [PDF]

				D. Toy, D. Kugler, M. Wolfson, T. V. Bos, J. Gurgel, J. Derry, J. Tocker, and J. Peschon Cutting Edge: Interleukin 17 Signals through a Heteromeric Receptor Complex J. Immunol., July 1, 2006; 177(1): 36 - 39. [Abstract] [Full Text] [PDF]

				J. C Hogan and J. M Stephens Effects of leukemia inhibitory factor on 3T3-L1 adipocytes J. Endocrinol., June 1, 2005; 185(3): 485 - 496. [Abstract] [Full Text] [PDF]

				F. Shen, M. J. Ruddy, P. Plamondon, and S. L. Gaffen Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-{alpha}-induced genes in bone cells J. Leukoc. Biol., March 1, 2005; 77(3): 388 - 399. [Abstract] [Full Text] [PDF]

				S. Yamazaki, T. Muta, S. Matsuo, and K. Takeshige Stimulus-specific Induction of a Novel Nuclear Factor-{kappa}B Regulator, I{kappa}B-{zeta}, via Toll/Interleukin-1 Receptor Is Mediated by mRNA Stabilization J. Biol. Chem., January 14, 2005; 280(2): 1678 - 1687. [Abstract] [Full Text] [PDF]

				X. K. Liu, X. Lin, and S. L. Gaffen Crucial Role for Nuclear Factor of Activated T Cells in T Cell Receptor-mediated Regulation of Human Interleukin-17 J. Biol. Chem., December 10, 2004; 279(50): 52762 - 52771. [Abstract] [Full Text] [PDF]

				M. J. Ruddy, F. Shen, J. B. Smith, A. Sharma, and S. L. Gaffen Interleukin-17 regulates expression of the CXC chemokine LIX/CXCL5 in osteoblasts: implications for inflammation and neutrophil recruitment J. Leukoc. Biol., July 1, 2004; 76(1): 135 - 144. [Abstract] [Full Text] [PDF]