ELEVATION OF INTRACELLULAR CAMP INHIBITS RHOA ACTIVATION AND INTEGRIN-DEPENDENT LEUKOCYTE ADHESION INDUCED BY CHEMOATTRACTANTS

Chemoattractant receptors of the serpentine, heterotrimeric G alpha(i) protein-linked family can activate leukocyte integrins and in this ro le regulate leukocyte traffic and cell-cell interactions in immune and inflammatory responses. Using a mouse lymphoid cell line transfected with human formyl peptide or interleukin-8 receptors and normal human neutrophils as models, we show that cAMP functions as a gating element on the chemoattractant-induced rho-dependent signaling pathway leadin g to leukocyte integrin activation and adhesion. cAMP, acting through protein kinase A, inhibits chemoattractant-triggered integrin-dependen t leukocyte adhesion. cAMP also prevents guanine nucleotide exchange o n RhoA, a small GTP-binding protein of the rho subfamily, which is act ivated in seconds by chemoattractants. In contrast, chemoattractant-tr iggered intracellular calcium elevation is unaffected by cAMP, and cAM P has no effect on rho-dependent adhesion and RhoA guanine nucleotide exchange triggered through the independent protein kinase C pathway. T hese data suggest that cAMP-induced inhibition of rho activation may b e responsible for the anti-adhesive effect of cAMP and may contribute to the anti-inflammatory activity of cAMP elevating agonists and drugs , Moreover, the findings extend the concept of cyclic nucleotide gatin g as a broadly important mechanism in the regulation of intracellular signaling pathways and the cellular activities they control.