The COX-2 inhibitor NS-398 causes T-cell developmental disruptions independent of COX-2 enzyme inhibition.
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the function of cyclooxygenases, COX-1 and COX-2, which catalyze the first step in the synthesis of inflammatory mediators (PGE2). We sought to understand the roles of cyclooxygenases and NSAIDs in T-cell development. Our data show no significant defects in T-cell development in fetal thymic organ cultures of mice disrupted in both or either COX genes or in mice disrupted in either EP-1 or EP-2 receptor genes. On the other hand, NSAIDs reproducibly caused thymocyte developmental defects. However, the specific effects of the COX-2 inhibitors were not correlated with their potency for inhibition of COX-2 activity. We focused on the NS-398 COX-2 inhibitor and showed that its effects could not be reversed by exogenous PGE2. Furthermore, NS-398 was inhibitory even when its target, COX-2, was absent. These data show that the T-cell developmental effects of NS-398 are COX-2 and PGE2 independent.
Xu
H
H
Jerome H. Holland Laboratory for Biomedical Research, American Red Cross, Rockville, MD 20855, USA.
Izon
D J
DJ
Loftin
C
C
Spain
L M
LM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000633:toxicity*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology*; D007153:Immunologic Deficiency Syndromes / Q000139:chemically induced*; D007213:Indomethacin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009578:Nitrobenzenes / Q000494:pharmacology / Q000633:toxicity*; D009924:Organ Culture Techniques; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018078:Receptors, Prostaglandin E / Q000172:deficiency / Q000235:genetics; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013449:Sulfonamides / Q000494:pharmacology / Q000633:toxicity*; D013601:T-Lymphocytes / Q000473:pathology*; D013876:Thiophenes / Q000494:pharmacology; D013950:Thymus Gland / Q000196:embryology / Q000276:immunology / Q000473:pathology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; C460873:N-(3-pyridyl)indomethacinamide; D009578:Nitrobenzenes; C545636:Ptger1 protein, mouse; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013449:Sulfonamides; D013876:Thiophenes; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C064874:DuP 697; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone; D007213:Indomethacin