Inhibition of the NF-kappaB signaling pathway mediates the anti-inflammatory effects of petrosaspongiolide M.
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.
Posadas
Inmaculada
I
Departamento de Farmacología, Facultad de Farmacia, Universidad de Valencia, Avda. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
Terencio
Maria Carmen
MC
Randazzo
Antonio
A
Gomez-Paloma
Luigi
L
Payá
Miguel
M
Alcaraz
Maria José
MJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D020672:I-kappa B Proteins; D007527:Isoenzymes; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D009573:Nitrites; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C118309:petrosaspongiolide m; D000072000:NF-KappaB Inhibitor alpha; D009828:Oleanolic Acid; D004247:DNA; D015054:Zymosan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone