Selective inhibitors of cyclooxygenase-2 delay the activation of nuclear factor kappa B and attenuate the expression of inflammatory genes in murine macrophages treated with lipopolysaccharide.
The effect of rofecoxib, a selective cyclooxygenase-2 inhibitor, on inflammatory signaling has been investigated in elicited murine peritoneal macrophages. Macrophages treated with 10 microM rofecoxib exhibited an important inhibition in the early activation of nuclear factor kappa B (NF-kappa B) and the mitogen-activated protein kinase p38, the extracellular-regulated kinase p44, and the c-Jun N-terminal kinase. Moreover, this drug decreased the protein levels of nitric-oxide synthase-2 and cyclooxygenase-2 in lipopolysaccharide (LPS)-treated macrophages. Rofecoxib delayed and attenuated NF-kappa B activation, which impaired significantly the expression of kappa B-dependent genes. This drug and related coxibs did not affect cell viability and protected against LPS-induced apoptosis through the impairment of the inflammatory response. These data show an additional anti-inflammatory mechanism of selective cyclooxygenase-2 inhibitors through the attenuation of macrophage activation.
Callejas
Nuria A
NA
Instituto de Bioquímica, Centro Mixto Consejo Superior de Investigaciones Cientificas-Universidad Complutense de Madrid, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Fernández-Martínez
Amalia
A
Castrillo
Antonio
A
Boscá
Lisardo
L
Martín-Sanz
Paloma
P
D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D051550:I-kappa B Kinase; D007527:Isoenzymes / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013450:Sulfones
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013450:Sulfones; C116926:rofecoxib; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse