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Published online before print February 5, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0807521

Received for publication August 7, 2007.
Revised November 7, 2007.
Accepted for publication December 4, 2007.

Article

LPS-induced up-regulation of TGF- 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 ^*@

*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

^@ To whom correspondence should be addressed. E-mail: paultam{at}hkucc.hku.hk.

	Abstract

The immunosuppressive activity of TGF--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- signaling by a specific inhibitor of the TGF- 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- 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- signaling via ALK5 on the regulation of TNF- synthesis.

Key Words: ALK5 • inflammation • septic shock