Small molecule disruption of G protein beta gamma subunit signaling inhibits neutrophil chemotaxis and inflammation.
G protein betagamma subunit-dependent signaling is important for chemoattractant-dependent leukocyte chemotaxis. Selective small molecule targeting of phosphoinositide 3-kinase (PI3-kinase) gamma catalytic activity is a target of interest for anti-inflammatory pharmaceutical development. In this study, we examined whether small-molecule inhibition of Gbetagamma-dependent signaling, including Gbetagamma-dependent activation of PI3-kinase gamma and Rac1, could inhibit chemoattractant-dependent neutrophil migration in vitro and inflammation in vivo. Small-molecule Gbetagamma 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 Gbetagamma-regulation may be an effective anti-inflammation strategy.
Lehmann
D M
DM
University of Rochester, Department of Pharmacology and Physiology, 601 Elmwood Ave., Box 711, Rochester, NY 14642, USA.
Seneviratne
A M P B
AM
Smrcka
A V
AV
D000818:Animals; D002464:Cell Migration Inhibition; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D004487:Edema / Q000378:metabolism / Q000517:prevention & control; D044387:GTP-Binding Protein beta Subunits / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D044388:GTP-Binding Protein gamma Subunits / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014966:Xanthenes / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D014966:Xanthenes; C007820:gallein