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Volume 272, Number 41, Issue of October 10, 1997 pp. 25693-25699
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation of Macrophage Cytokine Production by Prostaglandin E₂
DISTINCT ROLES OF CYCLOOXYGENASE-1 AND -2

(Received for publication, June 5, 1997, and in revised form, July 29, 1997)

From the Laboratory of Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

Prostaglandin E₂ (PGE₂) modulates a variety of physiological processes including the production of inflammatory cytokines. There are two cyclooxygenase (Cox) enzymes, Cox-1 and Cox-2, that are responsible for initiating PGE₂ synthesis. These isozymes catalyze identical biosynthetic reactions but are regulated by different mechanisms in the cell. This report examines differences in the roles of Cox-1 and Cox-2 in regulating cytokine synthesis in macrophages. We employed agents that selectively modulate the activity of each isozyme and measured their effects on synthesis of interleukin (IL)-6, IL-1, and tumor necrosis factor- by peritoneal macrophages. Among these three cytokines, only IL-6 synthesis was stimulated by production of endogenous PGE₂. This effect was specifically linked to activation of Cox-2 and not Cox-1. The specificity derives, partly, from the timing of the production of PGE₂ following stimulation of each isozyme and from induction of ancillary signals that control the response to PGE₂. The experimental findings demonstrate that the effects of Cox-1 and Cox-2 activity on macrophage IL-6 synthesis are segregated. This provides a mechanism for IL-6 to be induced selectively during inflammation.

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