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J Leukoc Biol. 2008 May;83(5):1165-73. doi: 10.1189/jlb.0807521. Epub 2008 Feb 5.

LPS-induced up-regulation of TGF-beta receptor 1 is associated with TNF-alpha expression in human monocyte-derived macrophages.

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Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, China.


The immunosuppressive activity of TGF-beta-mediated signaling is well documented, but in contrast, its ability to promote proinflammatory responses is less clear. In this study, we report that blockade of TGF-beta signaling by a specific inhibitor of the TGF-beta receptor I [activin receptor-like kinase 5 (ALK5)] SB431542 significantly reduces the production of TNF-alpha, a key proinflammatory cytokine, by LPS-stimulated human monocyte-derived macrophages. ALK5 protein was only detectable after LPS stimulation, and the failure of treatment with SB431542 to alter TNF-alpha mRNA expression indicates that regulation is post-transcriptional. The additive effect of blocking TGF-beta and p38 MAPK signaling on reducing TNF-alpha but not IL-6 production suggests that there is selectivity in pathway signaling. SB431542 had similar inhibitory effects on TNF-alpha production by human monocytes and endothelial cells as well as macrophages. Furthermore, treatment with SB431542 reduced plasma TNF-alpha levels and tissue damage and thereby, prevented the lethal effects of LPS in a mouse model of septic shock. Our data demonstrate a direct effect of TGF-beta signaling via ALK5 on the regulation of TNF-alpha synthesis.

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