IL-2 and IL-4 Stimulate MEK1 Expression and Contribute to T Cell Resistance against Suppression by TGF-β and IL-10 in Asthma

Abstract

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-β, 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-β, 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-β– 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.

Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma

“…24, 31, 32 This pathway induces the activating protein 1 (AP1) transcription factors, which antagonize glucocorticoids. Conversely, glucocorticoids antagonize AP1 by inducing GILZ.…”

“…33 We have previously reported that CD4 T cells from moderate to severe asthmatic patients have increased expression of MEK1. 24 Inhibition of MEK1 reverses T cell resistance against dexamethasone. We analyzed BAL CD4 T cells for MEK1 (referred to as MEK) expression and the sensitivity of MEK positive cells to dexamethasone.…”

“…50 We have previously shown that JunB is a MEK inducible protein. 24 Thus, IL4 high Th2 cells with a high level of JunB could, under Batf-inducing condition, (e.g. stimulation with IL1) begin to form complexes with Batf and IRF4, and lead to IL17 production.…”

“…Flow cytometry was performed using a CyAn ADP Analyzer 9 color flow cytometer (Beckman Coulter, Brea, CA) in the NJH Flow Core Facility as described previously. 24 Flow cytometry data were analyzed with the software FlowJo (Tree Star, Inc. Ashland, OR). We carefully gated only small and non-granular cells by forward and side scatters, respectively, and excluded the large and highly granular BAL cells from analysis as they tend to bind many antibodies non-specifically as reported previously.…”

The association between IFN-γ and IL-4 genetic polymorphisms and childhood susceptibility to bronchial asthma

“…Further correlation analysis of the polymorphism at −589 and the levels of IL-4 and total IgE show no correlation between them. Asthma is a complex disease, and apart from the many immunocytes and their cytokines that cause this disease (Bottema et al, 2010;Karwot et al, 2008;Liang et al, 2010;Xu et al, 2010), other factors affect IL-4 and total IgE levels.…”