RESUMO
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. CONCLUSION: 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.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Receptores Adrenérgicos beta 2/imunologia , Células Th2/imunologia , Adolescente , Agonistas Adrenérgicos beta/imunologia , Adulto , Antígenos CD/imunologia , Células Cultivadas , Quimiotaxia de Leucócito/imunologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/imunologia , Proteína Quinase Tipo II Dependente de AMP Cíclico , Proteínas Quinases Dependentes de AMP Cíclico/imunologia , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Fenoterol/imunologia , Humanos , Interferon gama/imunologia , Interleucina-4/imunologia , Interleucina-5/imunologia , Masculino , Pessoa de Meia-Idade , Fosforilação , RNA Mensageiro/análise , Células Th1/imunologia , Regulação para Cima , Quinases de Receptores Adrenérgicos betaAssuntos
Eritema Multiforme/induzido quimicamente , Exantema/induzido quimicamente , Fenoterol/efeitos adversos , Ativação Linfocitária/imunologia , Tocolíticos/efeitos adversos , Adulto , Eritema Multiforme/complicações , Eritema Multiforme/imunologia , Exantema/complicações , Exantema/imunologia , Feminino , Fenoterol/imunologia , Fenoterol/uso terapêutico , Humanos , Técnicas In Vitro , Interleucina-5/imunologia , Trabalho de Parto Prematuro/tratamento farmacológico , Gravidez , Tocolíticos/imunologia , Tocolíticos/uso terapêuticoRESUMO
The aim of the study was to investigate whether topical application of a beta-2-adrenostimulant (fenoterol) on the mucous membrane has a clinically significant anti-allergic effect. Thirty-three patients with grass pollen hay fever completed the trial which was a double-blind, placebo-controlled cross-over design. After a run-in period the patients received two puffs of 50 micrograms fenoterol 4 times a day or placebo for 21/2 weeks before cross-over. Symptoms were scored on diary cards and there was a moderate, but significant effect of fenoterol on sneezing, but the effect on secretion and blockage was insignificant. It is concluded that beta-2-stimulating agents are not competitors to the very effective topical steroids.
