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

W. H. Faour, N. Alaaeddine, A. Mancini, Q. W. He, D. Jovanovic, J. A. Di Battista
2005 Journal of Biological Chemistry  
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 E 2 (PGE 2 ) 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
more » ... irmed that PGE 2 induces egr-1 mRNA expression and protein synthesis by restricted SAPK2/p38 MAPKdependent 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 PGE 2 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 PGE 2 . 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. PGE 2 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 PGE 2 target gene that may be a key regulatory factor in mediating eicosanoid control of genes involved in the immune and inflammatory responses.
doi:10.1074/jbc.m414067200 pmid:15640148 fatcat:hrltig3bjfba3c72mtqvdgw5dq