Cross-talk between ERK and p38 MAPK mediates selective suppression of pro-inflammatory cytokines by transforming growth factor-β

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Abstract

Phagocytosis of apoptotic cells by macrophages results in the production of transforming growth factor-β (TGF-β), which plays an important role in induction of an anti-inflammatory phenotype and resolution of inflammation. In this study, we show that TGF-β prevents pro-inflammatory cytokine production through inhibition of p38 mitogen-activated protein kinase (MAPK) and NF-κB. Blockade of extracellular signal-regulated kinase (ERK) signaling by the MEK-1/2 inhibitor PD 98059 reversed the inhibitory effects of TGF-β, suggesting that cross-talk between MAPKs is essential for this response. Further investigation indicated that TGF-β activated ERK, which in turn up-regulated MAPK phosphatase-1, thereby inactivating p38 MAPK. On the other hand, TGF-β 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-β on lipopolysaccharide-stimulated SAPK/JNK phosphorylation along with a demonstrated inhibition of TGF-β-induced AP-1 activation by dominant-negative Smad3 suggest that TGF-β-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-β selectively inhibits inflammatory cytokine production through cross-talk between MAPKs.

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Xiao, Y. Q., Malcolm, K., Scott Worthen, G., Gardai, S., Schiemann, W. P., Fadok, V. A., … Henson, P. M. (2002). Cross-talk between ERK and p38 MAPK mediates selective suppression of pro-inflammatory cytokines by transforming growth factor-β. Journal of Biological Chemistry, 277(17), 14884–14893. https://doi.org/10.1074/jbc.M111718200

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