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

Abstract

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.

Sodium selenite inhibits the expression of VEGF, TGFβ1 and IL-6 induced by LPS in human PC3 cells via TLR4-NF-KB signaling blockage

“…RT-PCR results showed that LPS increased TGFβ 1 and VEGF expression after 3 h incubation, which consistent with previous reports [26,27]. Selenium pretreatment at all test concentrations (0.5-5 uM) markedly inhibited LPS-induced TGFβ 1 and VEGF mRNA expression (Fig.…”

UTL-5g Lowers Elevated Blood Levels of TNF-a and TGF-? and Increases Survival Rates in Animals Treated with LPS/D-(+)-galactosamine

“…In addition, blockade of TGF-β signaling significantly reduces the production of TNF- by LPS-stimulated human monocyte-derived macrophages [22]. The present work on UTL-5g is in line with these reports and indicates that UTL-5g may be worthy of further investigation as a potential agent for sepsis.…”

“…In addition, the reductions of both TNF- and TGF-β are generally parallel to the mouse survival pattern in the previous study. This is logical because LPSinduced up-regulation of TGF-β receptor is associated with TNF- expression and blockade of TGF-β signaling reduces the production of TNF- [22]. In addition, elevated TNF- levels induced by LPS are known to be associated with animal lethality [14,23].…”

NK Cell Tolerance to TLR Agonists Mediated by Regulatory T Cells after Polymicrobial Sepsis

“…The ex vivo CP procedure in il-10 2/2 mice showed a lower NK cell tolerance in some conditions but without reaching significance, suggesting a modest role of IL-10 in the tolerance of NK cells. Because the use of mice deficient for TGF-b was inappropriate in our model (54) and because the use of anti-TGF-b (28) was not satisfactory in our hands, we used a pharmacological specific inhibitor of TGF-b signaling (29). Its injection prior to CP led to a decreased tolerance of NK cells in terms of IFN-g and GM-CSF production, suggesting a link between the TGF-b and NK cells in sepsis.…”