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Kanyawim Kirtikara, Scott G. Morham^¶, Rajendra Raghow^*,,||, Stanley J. F. Laulederkind, Takuro Kanekura, Sarita Goorha^*, and Leslie R. Ballou^*,,

From the ^* Department of Veterans Affairs Medical Center, the Department of Medicine, the Department of Biochemistry, and the ^|| Department of Pharmacology, The University of Tennessee, Memphis, Tennessee 38163; and the ^¶ Department of Pathology, The University of North Carolina, Chapel Hill, North Carolina 27559

Prostaglandin E₂ (PGE₂) production in immortalized, nontransformed cells derived from wild-type, cyclooxygenase 1–deficient (COX-1^–/–) or cyclooxygenase 2–deficient (COX-2^–/–) mice was examined after treatment with interleukin (IL)-1β, tumor necrosis factor , acidic fibroblast growth factor, and phorbol ester (phorbol myristate acetate). Compared with their wild-type counterparts, COX-1^–/– or COX-2^–/– cells exhibited substantially enhanced expression of the remaining functional COX gene. Furthermore, both basal and IL-1–induced expression of cytosolic phospholipase A₂ (cPLA₂), a key enzyme-regulating substrate mobilization for PGE₂ biosynthesis, was also more pronounced in both COX-1^–/– and COX-2^–/– cells. Thus, COX-1^–/– and COX-2^–/– cells have the ability to coordinate the upregulation of the alternate COX isozyme as well as cPLA₂ genes to overcome defects in prostaglandin biosynthetic machinery. The potential for cells to alter and thereby compensate for defects in the expression of specific genes such as COX has significant clinical implications given the central role of COX in a variety of disease processes and the widespread use of COX inhibitors as therapeutic agents.

Address correspondence to Leslie R. Ballou, Department of Veterans Affairs Medical Center, Research Service (151), 1030 Jefferson Avenue, Memphis, TN 38104. Phone: 901-577-7283. Fax: 901-577-7273; E-mail: lballou{at}utmem1.utmem.edu

¹ Abbreviations used in this paper: AA, arachidonic acid; COX, cyclooxygenase; cPLA, cytosolic phospholipase; FGF, fibroblast growth factor; PG, prostaglandin; RIA, radioimmunoassay.

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