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Received for publication September 29, 2003.
Revised December 19, 2003.
Accepted for publication December 22, 2003.
ABSTRACT
To investigate the role of phospholipase C (PLC) in inflammatory processes, we tested U73122, a widely-employed 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 (IL-8) and leukotriene B4 (LTB4)-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 (LPS)-induced macrophage, lymphocyte infiltration and PGE2 production in a mouse peritonitis model, and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema in mice. These results implicate PLC-dependent signaling pathways in the development of acute and chronic inflammatory responses in vivo.
Key words:
Inflammation, U73122, a phospholipase C inhibitor, macrophage infiltration, mouse ear edema, paw edema
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