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Published online before print February 5, 2008

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(Journal of Leukocyte Biology. 2008;83:1165-1173.)
© 2008 by Society for Leukocyte Biology

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

Yan Chen^*, Christy S. K. Kam^*, Feng Qin Liu^*, Yan Liu^*, Vincent C. H. Lui^*, Jonathan R. Lamb and Paul K. H. Tam^*,1

^* Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, China; and
Easter Bush Veterinary Centre, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian, United Kingdom

¹Correspondence: Division of Paediatric Surgery, Department of Surgery, The University of Hong Kong, K15, Queen Mary Hospital, Pokfulam, Hong Kong SAR, P.R. China. E-mail: paultam{at}hkucc.hku.hk

The immunosuppressive activity of TGF-β-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-β signaling by a specific inhibitor of the TGF-β receptor I [activin receptor-like kinase 5 (ALK5)] SB431542 significantly reduces the production of TNF-, 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- mRNA expression indicates that regulation is post-transcriptional. The additive effect of blocking TGF-β and p38 MAPK signaling on reducing TNF- but not IL-6 production suggests that there is selectivity in pathway signaling. SB431542 had similar inhibitory effects on TNF- production by human monocytes and endothelial cells as well as macrophages. Furthermore, treatment with SB431542 reduced plasma TNF- 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-β signaling via ALK5 on the regulation of TNF- synthesis.

Key Words: ALK5 • inflammation • septic shock