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)
Joy A.
Williams
and
Emily
Shacter
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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