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J. Biol. Chem., Vol. 280, Issue 10, 9536-9546, March 11, 2005

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Early Growth Response Factor-1 Mediates Prostaglandin E₂-dependent Transcriptional Suppression of Cytokine-induced Tumor Necrosis Factor- Gene Expression in Human Macrophages and Rheumatoid Arthritis-affected Synovial Fibroblasts^*

Wissam H. Faour, Nada Alaaeddine¶, Arturo Mancini||, Qing Wen He**, Dragan Jovanovic**, and John A. Di Battista**

From the Department of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the ^¶Department of Pharmacology, University of Balamand, Tripoli 9616, Lebanon, and the Departments of ^**Medicine and ^||Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 1A1, Canada

Tumor necrosis factor- (TNF-) is a pleiotropic proinflammatory cytokine that modulates a broad range of inflammatory and immunological processes. We have investigated the potential immunomodulatory properties of prostaglandin E₂ (PGE₂) by examining the molecular mechanism by which the eicosanoid suppresses T-cell-derived interleukin-17 (IL-17)-induced TNF- mRNA expression and protein synthesis in human macrophages and rheumatoid arthritis-affected synovial fibroblasts. Initial studies confirmed that PGE₂ induces egr-1 mRNA expression and protein synthesis by restricted SAPK2/p38 MAPK-dependent activating transcription factor-2 (ATF-2) dimer transactivation of the egr-1 promoter as judged by studies using wild-type (WT) and deletion mutant egr-1 promoter constructs, Northern and Western blotting, and standard and supershift electrophoretic mobility shift analyses. Using human leukemic monocytic THP-1 cells stably transfected with WT and dominant-negative mutant expression constructs of Egr-1, cotransfected or not with a WT pTNF-615SVOCAT construct, we observed that PGE₂ inhibition of IL-17-stimulated TNF- mRNA expression and promoter activity was dependent on Egr-1 expression, as mutants of Egr-1, alone or in combination, markedly abrogated any inhibitory effect of PGE₂. Standard and supershift electrophoretic mobility shift analysis, signaling "decoy" overexpression studies, and pTNF-615SVOCAT promoter assays using WT and mutant promoter constructs revealed that IL-17-up-regulated promoter activity was largely dependent on ATF-2/c-Jun transactivation. PGE₂ suppression of IL-17-induced ATF-2/c-Jun transactivation and DNA binding was dependent on Egr-1-mediated inhibition of induced c-Jun expression. We suggest that egr-1 is an immediate-early PGE₂ target gene that may be a key regulatory factor in mediating eicosanoid control of genes involved in the immune and inflammatory responses.

Received for publication, December 14, 2004

^* This work was supported in part by the Canadian Institutes of Health Research, the Canadian Arthritis Network of Excellence, and the Arthritis Society of Canada (to J. A. D. B.). 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Div. of Rheumatology and Clinical Immunology, Royal Victoria Hospital, McGill University Health Centre, Rm. M11.22, 687 Pine Ave. W., Montreal, Quebec H3A 1A1, Canada. Tel.: 514-842-1231 (ext. 34401); Fax: 514-289-8542; E-mail: john.dibattista{at}mcgill.ca.

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