RESUMEN
The T cell-driven airway inflammation in chronic asthma is uninhibited and sustained. We examined the resistance of T cells from asthmatic patients against suppression by TGF-ß, IL-10 and glucocorticoids and explored its signaling mechanism. CD4(+)CD25(-) T cells from allergic asthmatic subjects demonstrated increased TCR-stimulated proliferation as compared with healthy and chronic obstructive pulmonary disease controls. This proliferation was resistant to inhibition by TGF-ß, IL-10, and dexamethasone and to anergy induction. CD4 T cells from asthmatic patients, but not chronic obstructive pulmonary disease, allergic rhinitis, and healthy subjects, showed increased expression of MEK1, heightened phosphorylation of ERK1/2, and increased levels of c-Fos. IL-2 and IL-4 stimulated the expression of MEK1 and c-Fos and induced T cell resistance. The inhibition of MEK1 reversed, whereas induced expression of c-Fos and JunB promoted T cell resistance against TGF-ß- and IL-10-mediated suppression. We have uncovered an IL-2- and IL-4-driven MEK1 induction mechanism that results in heightened ERK1/2 activation in asthmatic T cells and make them resistant to certain inhibitory mechanisms.
Asunto(s)
Asma/inmunología , Linfocitos T CD4-Positivos/inmunología , Interleucina-10/inmunología , Interleucina-2/inmunología , Interleucina-4/inmunología , MAP Quinasa Quinasa 1/biosíntesis , Factor de Crecimiento Transformador beta/inmunología , Adulto , Anciano , Asma/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Separación Celular , Anergia Clonal/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Expresión Génica , Regulación de la Expresión Génica , Humanos , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Activación de Linfocitos/inmunología , MAP Quinasa Quinasa 1/inmunología , Persona de Mediana Edad , Transducción de Señal/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Adulto JovenRESUMEN
Assessment of the lung mechanics is crucial in lung function studies. Commonly lung mechanics is achieved through measurement of the input impedance of the lung where the experimental data is ideal for the application of system identification techniques. This study proposes a new approach for investigating the severity of lung conditions and also evaluating the treatment progression. The proposed method is established based on linear parametric identification of lung input impedance in mice and is applied to normal and asthmatic models (including acute, tolerant and chronic asthma) as well as a pharmacological intervention model. Experimental findings confirm the effectiveness of the analysis technique applied here. We discuss the potential application of this method to analyses of human lung mechanics.