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Exposure to TARC alters ₂-adrenergic receptor signaling in human peripheral blood T lymphocytes

Departments of ¹Allergology, ²Hematology, ³Molecular Pharmacology and ⁴Pulmonology, University Medical Center Groningen, Groningen, The Netherlands

Submitted 20 September 2004 ; accepted in final form 27 February 2005

The ₂-adrenergic receptor (₂-AR) negatively regulates T cell activity through the activation of the G_s/adenylyl cyclase/cAMP pathway. 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 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 -arrestin. Moreover, TARC was able to induce Src-dependent serine phosphorylation of the ₂-AR as well as its association with GRK2 and -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 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 -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 -agonists promotes T cell-mediated inflammation in asthma.

cAMP-responsive element binding protein phosphorylation; Src kinases; G protein-coupled receptor kinase 2; -arrestin; thymus and activation-regulated chemokine

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