title: Cross-talk between ERK and p38 MAPK mediates selective suppression of pro-inflammatory cytokines by transforming growth factor-beta.
abstract: Phagocytosis of apoptotic cells by macrophages results in the production of transforming growth factor-beta (TGF-beta), which plays an important role in induction of an anti-inflammatory phenotype and resolution of inflammation. In this study, we show that TGF-beta prevents pro-inflammatory cytokine production through inhibition of p38 mitogen-activated protein kinase (MAPK) and NF-kappaB. Blockade of extracellular signal-regulated kinase (ERK) signaling by the MEK-1/2 inhibitor PD 98059 reversed the inhibitory effects of TGF-beta, suggesting that cross-talk between MAPKs is essential for this response. Further investigation indicated that TGF-beta activated ERK, which in turn up-regulated MAPK phosphatase-1, thereby inactivating p38 MAPK. On the other hand, TGF-beta maintained or slightly increased production of the CC chemokine MCP-1, which is regulated predominantly by AP-1. Although SB 203580, an inhibitor of p38 MAPK, and dominant-negative p38 MAPK both increased AP-1 transcription, lack of effect of TGF-beta on lipopolysaccharide-stimulated SAPK/JNK phosphorylation along with a demonstrated inhibition of TGF-beta-induced AP-1 activation by dominant-negative Smad3 suggest that TGF-beta-stimulated AP-1 activation was not caused by inhibition of p38 MAPK but rather through the activation of Smads. Our data provide evidence that TGF-beta selectively inhibits inflammatory cytokine production through cross-talk between MAPKs.
authors.affiliation: Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
authors.forename: Yi Qun
authors.initials: YQ
authors.lastname: Xiao
authors.forename: Ken
authors.initials: K
authors.lastname: Malcolm
authors.forename: G Scott
authors.initials: GS
authors.lastname: Worthen
authors.forename: Shyra
authors.initials: S
authors.lastname: Gardai
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Fadok
authors.forename: Donna L
authors.initials: DL
authors.lastname: Bratton
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
mesh_terms: D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D007093:Imidazoles; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011725:Pyridines; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580