REGULATION OF MACROPHAGE CYTOKINE PRODUCTION BY PROSTAGLANDIN E-2 - DISTINCT ROLES OF CYCLOOXYGENASE-1 AND CYCLOOXYGENASE-2

Prostaglandin E-2 (PGE(2)) modulates a variety of physiological proces ses including the production of inflammatory cytokines. There are two cyclooxygenase (Cox) enzymes, Cox-1 and Cox-2, that are responsible fo r initiating PGE(2) synthesis. These isozymes catalyze identical biosy nthetic reactions but are regulated by different mechanisms in the cel l. This report examines differ differences in the roles of Cox-1 and C ox-2 in regulating cytokine synthesis in macrophages. We employed agen ts that selectively modulate the activity of each isozyme and measured their effects on synthesis of interleukin (IL)-6, IL-1, and tumor nec rosis factor-alpha by peritoneal macrophages. Among these three cytoki nes, only IL-6 synthesis was stimulated by production of endogenous PG E(2). This effect was specifically linked to activation of Cox-2 and n ot Cox-1. The specificity derives, partly, from the timing of the prod uction of PGE(2) following stimulation of each isozyme and from induct ion of ancillary signals that control the response to PGE(2). The expe rimental findings demonstrate that the effects of Cox-1 and Cox-2 acti vity on macrophage IL-6 synthesis are segregated. This provides a mech anism for IL-6 to be induced selectively during inflammation.