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Inhibition of the NF-κB signaling pathway mediates the anti-inflammatory effects of petrosaspongiolide M

2003; Elsevier BV; Volume: 65; Issue: 5 Linguagem: Inglês

10.1016/s0006-2952(02)01659-3

1873-2968

Inmaculada Posadas, María Carmen Terencio, Antonio Randazzo, Luigi Gomez‐Paloma, Miguel Payá, María José Alcaraz,

Inflammatory mediators and NSAID effects

Petrosaspongiolide M (PT) is a potent secretory phospholipase A2 inhibitor and anti-inflammatory agent. This marine metabolite reduced the production of nitrite, prostaglandin E2, and tumor necrosis factor-α 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-α expression. Since nuclear factor-κB (NF-κB) 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-κB pathway since at 1 μM it strongly decreased NF-κB–DNA binding in response to zymosan, in mouse peritoneal macrophages. Our study also indicated that PT could interfere with a key step in NF-κB activation, the phosphorylation of IκBα, resulting in inhibition of IκBα degradation. The control of a wide range of mediators by PT suggests a potentially wide therapeutic spectrum for this marine metabolite in inflammatory conditions.