Inhibition of the NF-κB Signaling Pathway Mediates the Anti-inflammatory Effects of Petrosaspongiolide M

Petrosaspongiolide M (PT) is a potent secretory phospholipase A, inhibitor and anti-inflammatory agent. This marine metabolite reduced the production of nitrite, prostaglandin E,, and tumor necrosis factor-alpha in the Mouse air pouch injected with zymosan. These effects were also observed in mouse peritoneal macrophages stimulated with zymosan. Inhibition of these inflammatory mediators was related to reductions in inducible nitric oxide synthase, cyclo-oxygenase-2, and tumor necrosis factor-a expression. Since nuclear factor-kappaB (NF-kappaB) appears to play a central role in the transcriptional regulation of these proteins by macrophages, we investigated the effects of PT on this transcription factor. We found that PT was a potent inhibitor of the NF-kappaB pathway since at 1 muM it strongly decreased NF-kappaB-DNA binding in response to zymosan, in mouse peritoneal macrophages. Our study also indicated that PT could interfere with a key step ill NF-kappaB activation, the phosphorylation of IkappaBalpha, resulting in inhibition Of IkappaBalpha degradation. The control of a wide range of mediators by PT suggests a potentially wide therapeutic spectrum for this marine metabolite in inflammatory conditions.