Yin-yang: balancing act of prostaglandins with opposing functions to regulate inflammation.
For many years, cyclooxygenase-2 (COX-2), a critical enzyme for PG production, has been the favorite target for anti-inflammatory drug development. However, recent revelations regarding the adverse effects of selective COX-2 inhibitors have stimulated intense debate. Interestingly, in the early phase of inflammation, COX-2 facilitates inflammatory PG production while in the late phase it has anti-inflammatory effects. Moreover, although some PGs are proinflammatory, others have anti-inflammatory effects. Thus, it is likely that PGs with opposing effects maintain homeostasis, although the molecular mechanism(s) remains unclear. We report here that an inflammatory PG, PGD2, via its receptor, mediates the activation of NF-kappaB stimulating COX-2 gene expression. Most interestingly, an anti-inflammatory PG (PGA1) suppresses NF-kappaB activation and inhibits COX-2 gene expression. We propose that while pro- and anti-inflammatory PGs counteract each other to maintain homeostasis, selective COX-2 inhibitors may disrupt this balance, thereby resulting in reported adverse effects.
Mandal
Asim K
AK
Section on Developmental Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Zhang
Zhongjian
Z
Kim
Sung-Jo
SJ
Tsai
Pei-Chih
PC
Mukherjee
Anil B
AB
D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D015230:Prostaglandin D2 / Q000494:pharmacology; D011453:Prostaglandins / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D011454:Prostaglandins A / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D016328:NF-kappa B; D011453:Prostaglandins; D011454:Prostaglandins A; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D015230:Prostaglandin D2; C100573:prostaglandin A1