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Small Molecule Disruption of G Protein β Subunit Signaling Inhibits Neutrophil Chemotaxis and Inflammation

Departments of Pharmacology and Physiology (D.M.L., A.V.S.), and Pathology (A.M.P.B.S.), University of Rochester, Rochester, New York

G protein β subunit-dependent signaling is important for chemoattractant-dependent leukocyte chemotaxis. Selective small molecule targeting of phosphoinositide 3-kinase (PI3-kinase) catalytic activity is a target of interest for anti-inflammatory pharmaceutical development. In this study, we examined whether small-molecule inhibition of Gβ-dependent signaling, including Gβ-dependent activation of PI3-kinase and Rac1, could inhibit chemoattractant-dependent neutrophil migration in vitro and inflammation in vivo. Small-molecule Gβ inhibitors suppressed fMLP-stimulated Rac activation, superoxide production, and PI3-kinase activation in differentiated HL60 cells. These compounds also blocked fMLP-dependent chemotaxis in HL60 cells and primary human neutrophils. Systemic administration inhibited paw edema and neutrophil infiltration in a mouse carrageenan-induced paw edema model. Overall, the data demonstrate that targeting Gβ-regulation may be an effective anti-inflammation strategy.

Address correspondence to: A. V. Smrcka, University of Rochester, Department of Pharmacology and Physiology, 601 Elmwood Ave., Box 711, Rochester, NY 14642. E-mail: alan_smrcka{at}urmc.rochester.edu