Elevation of intracellular cAMP inhibits RhoA activation and integrin-dependent leukocyte adhesion induced by chemoattractants.
Chemoattractant receptors of the serpentine, heterotrimeric Galphai 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.
Laudanna
C
C
Department of Pathology, Stanford University, Stanford, California 94305, USA.
Campbell
J J
JJ
Butcher
E C
EC
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002630:Chemotactic Factors / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism* / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D016209:Interleukin-8 / Q000494:pharmacology; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D002630:Chemotactic Factors; D016023:Integrins; D016209:Interleukin-8; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003994:Bucladesine; D000242:Cyclic AMP; D019204:GTP-Binding Proteins