Post-receptorial mechanisms underlie functional disregulation of beta2-adrenergic receptors in lymphocytes from Multiple Sclerosis patients.
Increased density of beta2-adrenergic receptors has been demonstrated on peripheral blood mononuclear cells (PBMCs) from Multiple Sclerosis (MS) patients. In this study we found that isoproterenol reduces T-cell proliferation and IFNgamma secretion in PBMCs cultures from healthy controls and IFNbeta-treated but not untreated MS patients. Reduced expression levels of G protein coupled receptor kinase (GRK)2/3 (p < 0.05) and increased isoproterenol-induced cAMP accumulation (p < 0.0001) were found in PBMCs from all MS patients. Dibutyryl cAMP reduced the proliferation of PBMCs from all subgroups but in a slighter manner in untreated MS patients. We conclude that signalling through beta2-adrenergic receptors is chronically up-regulated but functionally uncoupled to immunoregulatory functions of lymphocytes from MS patients. Disregulation downstream the cAMP-associated signalling may underlie such a phenomenon.
Giorelli
Maurizio
M
Department of Neurologic and Psychiatric Sciences, University of Bari, I-70124 Bari, Italy. mgiorelli@libero.it
Livrea
Paolo
P
Trojano
Maria
M
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D003994:Bucladesine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000276:immunology*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D051552:beta-Adrenergic Receptor Kinases
D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D003994:Bucladesine; D007371:Interferon-gamma; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D007545:Isoproterenol