Regulation of nuclear factor kappaB activation by G-protein-coupled receptors.

Accumulating evidence indicates that G-protein-coupled receptors (GPCRs) play an active role in transcriptional regulation. In leukocytes, activation of receptors for several chemokines and classic chemoattractants has been associated with enhanced expression of proinflammatory cytokines and chemokines. GPCRs in endothelial and epithelial cells also regulate transcription and contribute to the expression of cytokines, adhesion molecules, and growth factors that are essential for extravasation of leukocytes and tissue repair. Nuclear factor (NF) kappaB is one of the most important transcription factors responsible for the expression of these proinflammatory genes. Recent studies have shown that GPCRs utilize several different pathways to activate NF-kappaB. These pathways differ from the ones induced by classic cytokines in that they are initiated by heterotrimeric G-proteins, but they converge to IkappaB phosphorylation and nuclear translocation/modification of the NF-kappaB proteins. GPCR-induced NF-kappaB activation provides an effective means for local expression of cytokine and growth factor genes due to the wide distribution of these receptors. Chemokine-induced, GPCR-mediated production of chemokines constitutes an autocrine regulatory mechanism for the growth of certain malignant tumors and enhances the recruitment of leukocytes to sites of inflammation.