当前位置： SCI文献检索 > EXPERIMENTAL CELL RESEARCH期刊下所有文献 > S632A3, a new glutarimide antibiotic, suppresses lipopolysaccharide-induced pro-inflammatory responses via inhibiting the activation of glycogen synthase kinase 3β.

S632A3, a new glutarimide antibiotic, suppresses lipopolysaccharide-induced pro-inflammatory responses via inhibiting the activation of glycogen synthase kinase 3β.

Abstract：

:Inflammatory mediators including inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6) contribute to the course of a variety of inflammatory diseases. S632A3 is a new member of the glutarimide antibiotics isolated from a cultured broth of Streptomyces hygroscopicus S632 with a potent NF-κB inhibitory activity. In the present study, we investigated the anti-inflammatory effects and the underlying molecular mechanism of S632A3 on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. S632A3 concentration-dependently inhibited LPS-induced NO and prostaglandin E(2) (PGE(2)) production through the suppression of iNOS and COX-2 at gene transcription levels. In addition, S632A3 suppressed NF-κB-dependent inflammatory responses by inhibiting the activation of glycogen synthase kinase 3β (GSK-3β), while the activation of IκB kinase (IKK) complex was unaffected. S632A3 suppressed NF-κB activity by differentially affecting the CREB (cAMP response element-binding protein) and NF-κB p65 interacting with the coactivator CBP (CREB binding protein). S632A3 also inhibited GSK-3β-elicited iNOS and COX-2 expression. Moreover, S632A3 was shown to inhibit the activation of ASK1 (Apoptosis-signal regulating kinase 1) and p38 mitogen-activated protein kinase, therefore attenuated the LPS-induced NF-κB activity in macrophages. Furthermore, S632A3 significantly reduced the pro-inflammatory cytokines TNF-α and IL-6 production while increased the anti-inflammatory cytokine IL-10 production in LPS-stimulated RAW264.7 cells. Our study thus provides a molecular mechanism by which S632A3 inhibited LPS-induced pro-inflammatory response in macrophages through interfering with the activation of GSK-3β and ASK1-p38 signaling.

journal_name

Exp Cell Res

journal_title

Experimental cell research

authors

Deng H,Zhang N,Wang Y,Chen J,Shen J,Wang Z,Xu R,Zhang J,Song D,Li D

doi

10.1016/j.yexcr.2012.08.008

subject

Has Abstract

pub_date

2012-12-10 00:00:00

pages

2592-603

issue

eissn

0014-4827

issn

1090-2422

pii

S0014-4827(12)00378-3

journal_volume

318

pub_type

杂志文章

在线工具

S632A3, a new glutarimide antibiotic, suppresses lipopolysaccharide-induced pro-inflammatory responses via inhibiting the activation of glycogen synthase kinase 3β.