COX-1 AND COX-2 TISSUE EXPRESSION - IMPLICATIONS AND PREDICTIONS

It has been proposed that cyclooxygenase (COX)-1 and COX-2 subserve di fferent physiologic functions largely because of the striking differen ces in their tissue expression and regulation. COX-1 displays the char acteristics of a ''housekeeping'' gene and is constitutively expressed in almost all tissues. COX-1 appears to be responsible for the produc tion of prostaglandins (PG) that are important for homeostatic functio ns, such as maintaining the integrity of the gastric mucosa, mediating normal platelet function, and regulating renal blood flow. In sharp c ontrast, COX-2 is the product of an ''immediate-early'' gene that is r apidly inducible and tightly regulated, Under basal conditions, COX-2 expression is highly restricted; however, COX-2 is dramatically upregu lated during inflammation. For example, synovial tissues in patients w ith rheumatoid arthritis (RA) express increased levels of COX-2. In an imal models of inflammatory arthritis, COX-2 increases in parallel wit h PG production and clinical inflammation. In vitro experiments have r evealed increased COX-2 expression after stimulation with proinflammat ory cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor- alpha (TNF-alpha), in many cell types, including synoviocytes, endothe lial cells, chondrocytes, osteoblasts, and monocytes/macrophages. Anot her distinguishing characteristic of COX-2 is decreased expression in response to glucocorticoids. COX-2 is also increased in some types of human cancers, particularly colon cancer. Mechanisms underlying the as sociation between COX-2 overexpression and tumorigenic potential may i nclude resistance to apoptosis, or programmed cell death. Upregulated COX-2 expression undoubtedly plays a role in pathologic processes char acterized by increased local PG production. One would predict, based o n current information regarding the differential tissue expression of COX-1 and COX-2, that highly selective inhibitors of COX-2 will provid e effective antiinflammatory activity with marked reduction in toxicit y.