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The Nora Eccles Harrison Cardiovascular Research and Training Institute,
The Eccles Program in Human Molecular Biology and Genetics, and the Departments of
Anatomy,
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Biochemistry,
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Medicine,
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Pathology, and
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Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84112
The synthesis of prostanoids is regulated by cyclooxygenases
(prostaglandin H synthases), which catalyze the conversion of
arachidonic acid to PGH2. Cyclooxygenases are the target of
aspirin and other nonsteroidal anti-inflammatory agents. In this
study, we found that human polymorphonuclear leukocytes (PMNs) express
the inducible isoform of cyclooxygenase, COX-2, when stimulated by LPS
whereas the protein was not detectable in freshly isolated human PMNs.
We also found by immunohistochemical analysis that COX-2 is expressed
in PMNs in inflamed human tissues. COX-2 was induced in a time- and
concentration-dependent fashion when isolated human PMNs were exposed
to LPS; COX-2 was also induced, or its expression was increased, by
TNF-
, IL-1, and IL-8. Expression of COX-2 in stimulated PMNs was
paralleled by secretion of PGE2. The release of
PGE2 was blocked by a selective nonsteroidal inhibitor of
COX-2, indicating that the enzyme is responsible for the prostanoids
produced, and was inhibited by dexamethasone. The time course of
LPS-induced COX-2 expression and other features were different in
freshly isolated PMNs, monocytes, and macrophages, indicating that
COX-2 expression is differentially regulated in myeloid cells of
different lineages and degrees of maturation. Consistent with this,
IL-4 and IL-10, which suppressed LPS-induced COX-2 expression in
monocytes, had little effect on this response by PMNs. These
experiments demonstrate that PMNs express COX-2 when appropriately
stimulated. Thus, they may actively influence the eicosanoid
composition of the acute inflammatory milieu.
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