G-PROTEIN-COUPLED SIGNAL-TRANSDUCTION PATHWAYS FOR INTERLEUKIN-8

Interleukin-8 (IL-8) is one of the major mediators of the inflammatory response. The pathways by which IL-8 activates inositide-specific pho spholipase C (PLC) were investigated by co-expression of different com ponents of the guanosine triphosphate binding protein (G protein) path way in COS-7 cells. Two distinct IL-8 receptors reconstituted ligand-d ependent activation of endogenous PLC when transfected together with t he G protein alpha subunits Galpha14, Galpha15, or Galpha16. However, reconstitution was not observed with cells that overexpressed Galpha(q ) or Galpha11. Furthermore, IL-8 receptors interacted with endogenous pertussis toxin-sensitive G proteins or with the recombinant G protein G(i) to release free betagamma subunits that could then specifically activate the beta2 isoform of PLC. These findings suggest that IL-8 ac ts through signal-transducing pathways that are limited to specific he terotrimeric G proteins and effectors. These may provide suitable targ ets for the development of anti-inflammatory agents.