Dual effects of acetylsalicylic acid on mast cell degranulation, expression of cyclooxygenase-2 and release of pro-inflammatory cytokines.
Several studies have demonstrated that nonsteroidal anti-inflammatory drugs, such as acetylsalicylic acid (ASA), can have inhibitory or enhancing effects on inflammatory cell function. These effects seem independent of cyclooxygenase activity and prostaglandin synthesis inhibition. Here, we examined the effect of ASA on bone marrow-derived mast cells in more detail. ASA blocked the expression of cyclooxygenase-2, the production of tumor necrosis factor-alpha and interleukin-6, and the release of granule mediators from mast cells in a concentration-dependent fashion. Concomitantly, ASA inhibited nuclear factor (NF)-kappaB activity, as well as the phosphorylation and breakdown of the inhibitory protein IkappaB-alpha. We thus propose that the anti-inflammatory effects of ASA in mast cells are due to suppression of IkappaB kinase activity, thereby inhibiting subsequent phosphorylation and degradation of IkappaB-alpha, activation of NF-kappaB, and transcription of proinflammatory cytokines. The inhibition of BMMC degranulation was independent of NF-kappaB activation, however. Interestingly, the expression of cyclooxygenase-2 was not inhibited at 1mM ASA, but was even enhanced significantly. The latter might contribute to the adverse effects of ASA in ASA-sensitive asthmatics.
Mortaz
Esmaeil
E
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
Redegeld
Frank A
FA
Nijkamp
Frans P
FP
Engels
Ferdi
F
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology; D015550:Cell Degranulation / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015850:Interleukin-6 / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin