Differential inhibitory effects of inotilone on inflammatory mediators, inducible nitric oxide synthase and cyclooxygenase-2, in LPS-stimulated murine macrophage

✍ Scribed by Yu-Ching Kuo; Ching-Shu Lai; Ju-Ming Wang; Vladimir Badmaev; Kalyanam Nagabhushanam; Chi-Tang Ho; Min-Hsiung Pan

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 410 KB
• Volume: 53
• Category: Article
• ISSN: 1613-4125
• DOI: 10.1002/mnfr.200800583

✦ Synopsis

Abstract

The inhibitory effects of inotilone and methylinotilone on the induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2) in murine RAW 264.7 cells activated with LPS were investigated. The results show that both hydroxyl groups on the benzene ring of the inotilone molecule are required for better anti‐inflammatory effect. Western blotting and RT‐PCR analyses demonstrated that inotilone blocked protein and mRNA expression of iNOS but not COX‐2. Instead, inotilone inhibited prostaglandin E~2~ production through decreasing the enzyme activity of COX‐2. The repression of iNOS but not COX‐2 expression may come from the differential effect of inotilone on nuclear factor‐κB (NFκB) and CCAAT/enhancer‐binding protein beta Treatment with inotilone resulted in the reduction of LPS‐induced nuclear translocation of NFκB subunit and the NFκB‐dependent transcriptional activity by blocking phosphorylation of inhibitor κB(IκB)α and p65 and subsequent degradation of inhibitor κBα. Inotilone also inhibited LPS‐induced activation of PI3K/Akt and extracellular signal‐regulated kinase 1/2 and p38 mitogen‐activated protein kinase. Our results suggest that inotilone may have potential to be developed into an effective anti‐inflammatory agent.