Exposure to TARC alters beta2-adrenergic receptor signaling in human peripheral blood T lymphocytes.
The beta(2)-adrenergic receptor (beta(2)-AR) negatively regulates T cell activity through the activation of the G(s)/adenylyl cyclase/cAMP pathway. beta(2)-AR desensitization, which can be induced by its phosphorylation, may have important consequences for the regulation of T cell function in asthma. In the present study we demonstrate that the C-C chemokine thymus and activation-regulated chemokine (TARC) impairs the ability of beta(2)-agonist fenoterol to activate the cAMP downstream effector cAMP-responsive element binding protein (CREB) in freshly isolated human T cells. The TARC-induced activation of Src kinases resulted in membrane translocation of both G protein-coupled receptor kinase (GRK) 2 and beta-arrestin. Moreover, TARC was able to induce Src-dependent serine phosphorylation of the beta(2)-AR as well as its association with GRK2 and beta-arrestin. Finally, in contrast to CREB, phosphorylation of Src and extracellular signal-regulated kinase was enhanced by fenoterol upon TARC pretreatment. In summary, we show for the first time that TARC exposure impairs beta(2)-AR function in T cells. Our data suggest that this is mediated by Src-dependent activation of GRK2, resulting in receptor phosphorylation, binding to beta-arrestin, and a switch from cAMP-dependent signaling to activation of the MAPK pathway. We propose that aberrant T cell control in the presence of endogenous beta-agonists promotes T cell-mediated inflammation in asthma.
Heijink
Irene H
IH
Department of Allergology, University Medical Center Groningen, The Netherlands.
Vellenga
Edo
E
Oostendorp
Jaap
J
de Monchy
Jan G R
JG
Postma
Dirkje S
DS
Kauffman
Henk F
HF
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism; D001249:Asthma / Q000378:metabolism; D050882:CREB-Binding Protein; D002478:Cells, Cultured; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005280:Fenoterol / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009687:Nuclear Proteins / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D051552:beta-Adrenergic Receptor Kinases; D019061:src-Family Kinases / Q000378:metabolism
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D019390:Arrestins; C106230:CCL17 protein, human; D054414:Chemokine CCL17; D019742:Chemokines, CC; D009687:Nuclear Proteins; D018343:Receptors, Adrenergic, beta-2; D015534:Trans-Activators; D005280:Fenoterol; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases