title: 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.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, #1 Tian Tan Xi Li, Beijing 100050, China. hdeng@imb.pumc.edu.cn
authors.forename: Hongbin
authors.initials: H
authors.lastname: Deng
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jinjing
authors.initials: J
authors.lastname: Chen
authors.forename: Jiajia
authors.initials: J
authors.lastname: Shen
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.forename: Jingpu
authors.initials: J
authors.lastname: Zhang
authors.forename: Danqing
authors.initials: D
authors.lastname: Song
authors.forename: Diandong
authors.initials: D
authors.lastname: Li
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D010881:Piperidones / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010881:Piperidones; D047428:Protein Kinase Inhibitors; C511904:S632A3; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C007864:glutarimide