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

6533b7d4fe1ef96bd1263430

RESEARCH PRODUCT

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

Antonio Randazzo Inmaculada Posadas María Carmen Terencio Luigi Gomez-paloma Miguel Payá María José Alcaraz

subject

medicine.medical_treatment Anti-Inflammatory Agents Nitric Oxide Synthase Type II Biochemistry Dinoprostone Mice chemistry.chemical_compound Phospholipase A2 NF-KappaB Inhibitor alpha Cell Movement medicine Animals RNA Messenger Oleanolic Acid Phosphorylation Nitrites Pharmacology biology Tumor Necrosis Factor-alpha Zymosan NF-kappa B Zymosan Biological Transport NF-κB DNA Cell biology Isoenzymes Nitric oxide synthase IκBα Cytokine chemistry Biochemistry Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases Models Animal Macrophages Peritoneal biology.protein Cytokines I-kappa B Proteins Tumor necrosis factor alpha Nitric Oxide Synthase Signal Transduction Prostaglandin E

description

Petrosaspongiolide M (PT) is a potent secretory phospholipase A(2) inhibitor and anti-inflammatory agent. This marine metabolite reduced the production of nitrite, prostaglandin E(2), 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-alpha 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 microM 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 in 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.

year	journal	country	edition	language
2003-03-01

10.1016/s0006-2952(02)01659-3 http://hdl.handle.net/11588/205507