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Despite Transcriptional and Functional Coordination, Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Largely Reside in Distinct Lipid Microdomains in WISH Epithelial Cells

William E. Ackerman, IV, John M. Robinson and Douglas A. Kniss

Department of Obstetrics and Gynecology (Laboratory of Perinatal Research and Division of Maternal-Fetal Medicine) (WEA,DAK), Center for Biomedical Engineering (DAK), and Department of Physiology and Cell Biology (JMR), The Ohio State University, Columbus, Ohio

Correspondence to: Douglas A. Kniss, Laboratory of Perinatal Research, Department of Obstetrics and Gynecology, The Ohio State University, 5th Floor Means Hall, 1654 Upham Drive, Columbus, OH 43210. E-mail: kniss.1{at}osu.edu

Cytokine-induced prostaglandin (PG)E₂ synthesis requires increased expression of cyclooxygenase-2 (COX-2) in human WISH epithelial cells. Recently, an inducible downstream PGE synthase (microsomal PGE synthase-1, mPGES-1) has been implicated in this inflammatory pathway. We evaluated cooperation between COX-2 and mPGES-1 as a potential mechanism for induced PGE₂ production in WISH cells. Cytokine stimulation led to increased expression of both enzymes. Selective pharmacological inhibition of these enzymes demonstrated that induced PGE₂ release occurred through a dominant COX-2/mPGES-1 pathway. Unexpectedly, immunofluorescent microscopy revealed that the expression of these enzymes was not tightly coordinated among cells after cytokine challenge. Within cells expressing high levels of both mPGES-1 and COX-2, immunolabeling of high-resolution semithin cryosections revealed that COX-2 and mPGES-1 were largely segregated to distinct regions within continuous intracellular membranes. Using biochemical means, it was further revealed that the majority of mPGES-1 resided within detergent-insoluble membrane fractions, whereas COX-2 was found only in detergent-soluble fractions. We conclude that although mPGES-1 and COX-2 show transcriptional and functional coordination in cytokine-induced PGE₂ synthesis, complementary morphological and biochemical data suggest that a majority of intracellular mPGES-1 and COX-2 are segregated to discrete lipid microdomains in WISH epithelial cells. (J Histochem Cytochem 53:1391–1401, 2005)

Key Words: inflammation • cytokines • prostaglandin E₂ • cyclooxygenase-2 • microsomal prostaglandin E • synthase-1 • lipid microdomains • epithelial cells

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