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INFLAMMATION AND IMMUNOPHARMACOLOGY

In Vivo Activity of a Phospholipase C Inhibitor, 1-(6-((17-3-Methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122), in Acute and Chronic Inflammatory Reactions

Department of Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, New Jersey

To investigate the role of phospholipase C (PLC) in inflammatory processes, we tested 1-(6-((17-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122), a widely used PLC inhibitor, in several in vitro and in vivo assays. We first examined the effects of U73122 on human phospholipase C- (PLC-) isozymes and found that U73122 significantly inhibited recombinant human PLC-2, with an IC₅₀ of 6 µM. U73122 had little effect on PLC-1, PLC-3, or PLC-4. Consistent with its ability to inhibit PLC-2 enzymatic activity, U73122 reduced interleukin-8 and leukotriene B₄-induced Ca²⁺ flux and chemotaxis in human neutrophils in a concentration-dependent manner. In vivo, U73122 blocked carrageenan-induced hind paw edema in rats, carrageenan-induced macrophage and lymphocyte accumulation into subcutaneous chambers in dogs, lipopolysaccharide-induced macrophage, lymphocyte infiltration and prostaglandin E₂ production in a mouse peritonitis model, and 12-O-tetradecanoylphorbol-13-acetate-induced ear edema in mice. These results implicate PLC-dependent signaling pathways in the development of acute and chronic inflammatory responses in vivo.

Address correspondence to: Dr. Cuifen Hou, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., Drug Discovery, 1000 Route 202, Rm B-110, P.O. Box 300, Raritan, NJ 08869. E-mail: chou{at}prdus.jnj.com

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