LPS-induced up-regulation of TGF-beta receptor 1 is associated with TNF-alpha expression in human monocyte-derived macrophages.
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.
Chen
Yan
Y
Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, China.
Kam
Christy S K
CS
Liu
Feng Qin
FQ
Liu
Yan
Y
Lui
Vincent C H
VC
Lamb
Jonathan R
JR
Tam
Paul K H
PK
D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D016207:Cytokines; D017931:DNA Primers; D008070:Lipopolysaccharides; D018125:Receptors, Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse