In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of JUN N-terminal kinase and failure of prednisolone to inhibit JUN N-terminal kinase phosphorylation.

Abstract

Corticosteroid-resistant (CR) asthma is associated with increased in vitro activity of the proinflammatory transcription factor activating peptide (AP)-1 in PBMCs resulting from increased c-FOS synthesis. Increased AP-1 may sequester the glucocorticoid receptor to produce a CR state. Using the tuberculin-induced inflammatory responses in the skin, we have previously demonstrated that a therapeutically effective dose of prednisolone suppressed T-cell, macrophage, and eosinophil infiltration into purified protein derivative-induced lesional skin of corticosteroid-sensitive (CS), but not CR, individuals. Skin biopsy specimens from a tuberculin-induced model of dermal inflammation have been evaluated for the effect of corticosteroids in regulating components of AP-1 in vivo. Immunohistochemical analysis of the tuberculin-mediated cutaneous response has been performed on 9 subjects with CS asthma and 6 subjects with CR asthma for the regulatory components of AP-1 before and after 9 days of either 40 mg prednisolone or placebo. Significantly greater expression of c-FOS, phosphorylated c-JUN, and phosphorylated JUN N-terminal kinase (JNK) protein has been identified in CR than in CS subjects. Corticosteroids suppressed phosphorylation of c-JUN and JNK in the CS Group (P =.004 for both) but enhanced phosphorylation of c-JUN and JNK in the CR group (P =.031 for both). Resistance to corticosteroids in asthmatic subjects may be caused, at least in part, by failure to suppress JNK phosphorylation, leading to failure to suppress c-JUN N-phosphorylation. Increased JNK may be one of the mechanisms central to the mechanism of CR asthma.