Cacospongionolide B suppresses the expression of inflammatory enzymes and tumour necrosis factor-alpha by inhibiting nuclear factor-kappa B activation.
1. The marine product cacospongionolide B, a sesterterpene isolated from the Mediterranean sponge Fasciospongia cavernosa, is an inhibitor of secretory phospholipase A(2) with anti-inflammatory properties. In this work, we have studied the mechanism of action of this compound in the inflammatory response induced by zymosan in primary cells and in the mouse air pouch. 2. In mouse peritoneal macrophages, cacospongionolide B was able to downregulate the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), resulting in decreased production of NO and prostaglandin E(2) (PGE(2)). This compound also reduced tumour necrosis factor-alpha (TNF-alpha) mRNA expression and TNF-alpha levels. 3. Cacospongionolide B inhibited nuclear factor-kappaB (NF-kappaB)-DNA binding activity and the nuclear translocation of this transcription factor. 4. Treatment of cells with cacospongionolide B impaired NF-kappaB inhibitory protein (IkappaB-alpha) phosphorylation and enhanced IkappaB-alpha expression. 5. Inhibition of iNOS, COX-2 and inflammatory mediators was confirmed in the mouse air pouch. 6. These results show that cacospongionolide B is able to control NO, PGE(2) and TNF-alpha production in vitro and in vivo, effects likely dependent on NF-kappaB inhibition.
Departamento de Farmacologia, Facultad de Farmacia, Universidad de Valencia, Avda Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
Inmaculada
I
Posadas
Salvatore
S
De Rosa
M Carmen
MC
Terencio
Miguel
M
Payá
M José
MJ
Alcaraz
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011161:Porifera / Q000737:chemistry; D011714:Pyrans / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D011714:Pyrans; D014409:Tumor Necrosis Factor-alpha; C098384:cacospongionolide B; D015107:4-Butyrolactone