Elevation of Intracellular cAMP Inhibits RhoA Activation and Integrin-dependent Leukocyte Adhesion Induced by Chemoattractants

• Published in: The Journal of biological chemistry 1997-09, Vol.272 (39), p.24141-24144
• Main Authors: Laudanna, Carlo, Campbell, James J., Butcher, Eugene C.
• Format: Article
• Language: English
• Subjects: Adult; Amino Acid Sequence; Animals; Bucladesine - pharmacology; Cell Adhesion - drug effects; Cell Line; Chemotactic Factors - pharmacology; Cyclic AMP - metabolism; Cyclic AMP - physiology; GTP-Binding Proteins - metabolism; Humans; Integrins - metabolism; Interleukin-8 - pharmacology; Leukocytes - cytology; Leukocytes - drug effects; Leukocytes - metabolism; Mice; Molecular Sequence Data; N-Formylmethionine Leucyl-Phenylalanine - pharmacology; Signal Transduction - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.39.24141

Chemoattractant receptors of the serpentine, heterotrimeric Gαi protein-linked family can activate leukocyte integrins and in this role 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 leading to leukocyte integrin activation and adhesion. cAMP, acting through protein kinase A, inhibits chemoattractant-triggered integrin-dependent leukocyte adhesion. cAMP also prevents guanine nucleotide exchange on RhoA, a small GTP-binding protein of the rho subfamily, which is activated in seconds by chemoattractants. In contrast, chemoattractant-triggered intracellular calcium elevation is unaffected by cAMP, and cAMP has no effect on rho-dependent adhesion and RhoA guanine nucleotide exchange triggered through the independent protein kinase C pathway. These data suggest that cAMP-induced inhibition of rho activation may be 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 gating as a broadly important mechanism in the regulation of intracellular signaling pathways and the cellular activities they control.