Anti-Inflammatory Effect of Methylpenicinoline from a Marine Isolate of Penicillium sp (SF-5995): Inhibition of NF-κB and MAPK Pathways in Lipopolysaccharide-Induced RAW264.7 Macrophages and BV2 Microglia

In the course of a search for anti-inflammatory metabolites from marine-derived fungi, methylpenicinoline (1) was isolated from a marine isolate of Penicillin sp. Compound 1 inhibited lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production by suppressing the expression of inducible NO synthase (iNOS) in RAW264.7 macrophages and BV2 microglia. It also attenuated prostaglandin E-2 (PGE(2)) production by suppressing cyclooxygenase-2 (COX-2) expression in a concentration-dependent manner (from 10 mu M to 80 mu M) without affecting cell viability. In addition, compound 1 reduced the production of the pro-inflammatory cytokine interleukin-1 beta (IL-1 beta). In a further study designed to elucidate the mechanism of its anti-inflammatory effects, compound 1 was shown to block nuclear factor-kappa B (NF-kappa B) activation in LPS-induced RAW264.7 macrophages and BV2 microglia by inhibiting the phosphorylation of inhibitor kappa B-alpha (I kappa B-alpha), thereby suppressing the nuclear translocation of NF-kappa B dimers, namely p50 and p65, that are known to be crucial molecules associated with iNOS and COX-2 expression. In addition, compound 1 inhibited the activation of mitogen-activated protein kinase (MAPK) pathways. Taken together, the results suggest that compound 1 might be a valuable therapeutic agent for the treatment of anti-inflammatory and anti-neuroinflammatory diseases.