Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 279, Issue 33, Pages 34256-34268Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M402594200
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- NCI NIH HHS [CA 77839] Funding Source: Medline
- NCRR NIH HHS [RR 00095] Funding Source: Medline
- NICHD NIH HHS [HD 12304, HD 33994] Funding Source: Medline
- NIDA NIH HHS [DA 06668] Funding Source: Medline
- NIDDK NIH HHS [DK 48831] Funding Source: Medline
- NIGMS NIH HHS [GM 15431] Funding Source: Medline
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Comprehensive studies of prostaglandin ( PG) synthesis in murine resident peritoneal macrophages ( RPM) responding to bacterial lipopolysaccharide (LPS) revealed that the primary PGs produced by RPM were prostacyclin and PGE(2). Detectable increases in net PG formation occurred within the first hour, and maximal PG formation had occurred by 6 - 10 h after LPS addition. Free arachidonic acid levels rose and peaked at 1 - 2 h after LPS addition and then returned to baseline. Cyclooxygenase-2 (COX-2) and microsomal PGE synthase levels markedly increased upon exposure of RPM to LPS, with the most rapid increases in protein expression occurring 2 - 6 h after addition of the stimulus. RPM constitutively expressed high levels of COX-1. Studies using isoform-selective inhibitors and RPM from mice bearing targeted deletions of ptgs-1 and ptgs-2 demonstrated that COX-1 contributes significantly to PG synthesis in RPM, especially during the initial 1 - 2 h after LPS addition. Selective inhibition of either COX isoform resulted in increased secretion of tumor necrosis factor-alpha ( TNF-alpha); however, this effect was much greater with the COX-1 than with the COX-2 inhibitor. These results demonstrate autocrine regulation of TNF-alpha secretion by endogenous PGs synthesized primarily by COX-1 in RPM and suggest that COX-1 may play a significant role in the regulation of the early response to endotoxemia.
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