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Journal of Lipid Research, Vol. 46, 1027-1037, May 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

RAW264.7 cells lack prostaglandin-dependent autoregulation of tumor necrosis factor- secretion

Carol A. Rouzer^1,*,,,**, Aaron T. Jacobs^*,,,**, Chetan S. Nirodi^*,,,**, Philip J. Kingsley^*,,,**, Jason D. Morrow^, and Lawrence J. Marnett^*,,,**

^* Departments of Biochemistry and Chemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146
Vanderbilt Institute for Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146
Center for Pharmacology and Drug Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146
^** Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146
Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146

¹ To whom correspondence should be addressed. e-mail: c.rouzer{at}vanderbilt.edu

Studies of the response of RAW264.7 cells (RAW) to lipopolysaccharide (LPS) were carried out to determine why these cells do not demonstrate the prostaglandin (PG)-dependent autocrine regulation of tumor necrosis factor- (TNF-) secretion observed in primary resident peritoneal macrophages (RPMs). The major cyclooxygenase (COX) product of LPS-stimulated RAW was PGD₂, with lesser amounts of PGE₂. LPS-treated RAW produced PGs more slowly and reached their maximal PG synthetic rate later than did LPS-treated RPMs, as a result of lower constitutive COX-1 expression and a slower rate of COX-2 induction. Cytosolic phospholipase A₂ and levels of free arachidonic acid were similar in RAW and RPMs. In contrast to RPMs, LPS-treated RAW produced high quantities of TNF-, which were not altered in the presence of COX inhibitors. This failure of endogenous PGs to suppress TNF- secretion was explained by the absence of the prostaglandin D₂ receptor and the low levels of PGE₂ produced during the first 2 h of the LPS response.

These studies demonstrate that autocrine regulation of TNF- secretion in response to LPS is greatly facilitated by a COX-1-mediated rapid accumulation of PGs as well by a correspondence between the PGs produced and the receptors expressed by the cells.

Abbreviations: ATCC, American Type Culture Collection; COX, cyclooxygenase; cPGI₂, carbaprostacyclin; cPLA₂, cytosolic phospholipase A₂; LC/MS/MS, liquid chromatography/tandem mass spectrometry; LPS, lipopolysaccharide; mPGES-1, microsomal prostaglandin E synthase-1; PG, prostaglandin; PGI₂, prostacyclin; RAW, RAW264.7 cells; RPM, resident peritoneal macrophage; TNF-, tumor necrosis factor-; 20:4, arachidonic acid

Supplementary key words macrophage • lipopolysaccharide • cyclooxygenase-1 • cyclooxygenase-2 • arachidonic acid • cytosolic phospholipase A₂

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