PeproTech Inc.
Originally published online as doi:10.1189/jlb.0807521 on February 5, 2008

Published online before print February 5, 2008
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.0807521v1
83/5/1165    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chen, Y.
Right arrow Articles by Tam, P. K. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, Y.
Right arrow Articles by Tam, P. K. H.
(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-{alpha} expression in human monocyte-derived macrophages

Yan Chen*, Christy S. K. Kam*, Feng Qin Liu*, Yan Liu*, Vincent C. H. Lui*, Jonathan R. Lamb{dagger} 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
{dagger} 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-{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-β 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-β signaling via ALK5 on the regulation of TNF-{alpha} synthesis.

Key Words: ALK5 • inflammation • septic shock