NONSTEROIDAL ANTIINFLAMMATORY DRUGS CAUSE APOPTOSIS AND INDUCE CYCLOOXYGENASES IN CHICKEN-EMBRYO FIBROBLASTS

Programmed cell death (apoptosis) is an intrinsic part of organismal d evelopment and aging, Here we report that many nonsteroidal antiinflam matory drugs (NSAIDs) cause apoptosis when applied to v-src-transforme d chicken embryo fibroblasts (CEFs). Cell death was characterized by m orphological changes, the induction of tissue transglutaminase, and au todigestion of DNA. Dexamethasone, a repressor of cyclooxygenase (COX) 2, neither induced apoptosis nor altered the NSAID effect. Prostaglan din E(2), the primary eicosanoid made by CEFs, also failed to inhibit apoptosis. Expression of the protooncogene bcl-2 is very low in CEFs a nd is not altered by NSAID treatment. In contrast, p20, a protein that may protect against apoptosis when fibroblasts enter Go phase, was st rongly repressed. The NSAID concentrations used here transiently inhib it COXs. Nevertheless, COX-1 and COX-2 mRNAs and COX-2 protein were in duced, In some cell types, then, chronic NSAID treatment may lead to i ncreased, rather than decreased, COX activity and, thus, exacerbate pr ostaglandin-mediated inflammatory effects. The COX-2 transcript is a p artially spliced and nonfunctional form previously described. Thus, th ese findings suggest that COXs and their products play key roles in pr eventing apoptosis in CEFs and perhaps other cell types.