Altered beta2-adrenergic regulation of T cell activity after allergen challenge in asthma.
BACKGROUND
Airway inflammation in asthma is orchestrated by recruitment of T helper (Th)2 lymphocytes to the lung and subsequent production of Th2-like cytokines upon allergen challenge.


OBJECTIVE
To examine whether allergen-induced dysfunction of the beta2-adrenergic receptor (beta2-AR) contributes to the enhanced T(h2) cell activity in asthma.


METHODS
Beta2-adrenergic regulation of cytokine mRNA expression was studied in alpha-CD3/alpha-CD28-activated peripheral blood lymphocytes from seven asthma patients before and 6 h after allergen challenge, in conjunction with the effects of beta2-agonist fenoterol on T cell chemotaxis and signalling pathways.


RESULTS
A complete loss of beta2-AR control over expression of the Th2 cytokines IL-4, IL-5 and IL-13, but not of the Th1 cytokine IFN-gamma, was observed after allergen challenge. Furthermore, we found impaired beta2-AR regulation of T cell migration as well as signal transduction pathways, i.e. the phosphorylation of cyclic adenosine monophosphate-responsive element binding protein and the inhibition of the mitogen-activated protein kinase pathway. The loss of beta2-AR control was associated with increased beta-adrenergic receptor kinase expression, which might be involved in beta2-AR desensitization. In addition, we demonstrate for the first time that T cells exposed to the chemokine thymus and activation-regulated chemokine show hyporesponsiveness to fenoterol.


CONCLUSIONS
Our results suggest that allergen-induced loss of beta2-AR control, possibly mediated by chemokine release, plays an important role in enhanced Th2-like activity in asthma.
Heijink
I H
IH
Department of Allergology, University Hospital Groningen, Groningen, The Netherlands.
van den Berge
M
M
Vellenga
E
E
de Monchy
J G R
JG
Postma
D S
DS
Kauffman
H F
HF
D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000276:immunology; D000328:Adult; D000485:Allergens / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D001249:Asthma / Q000276:immunology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D005280:Fenoterol / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D018343:Receptors, Adrenergic, beta-2 / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D015854:Up-Regulation; D051552:beta-Adrenergic Receptor Kinases
D000318:Adrenergic beta-Agonists; D000485:Allergens; D015703:Antigens, CD; D017362:Cyclic AMP Response Element-Binding Protein; D015848:Interleukin-5; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D015847:Interleukin-4; D005280:Fenoterol; D007371:Interferon-gamma; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D048049:Extracellular Signal-Regulated MAP Kinases