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

Background: Corticosteroid-resistant (CR) asthma is associated with increas ed in vitro activity of the proinflammatory transcription factor activating peptide (AP)-1 in PBMCs resulting from increased c-POS synthesis. Increase d AP-1 may sequester the glucocorticoid receptor to produce a CR state. Usi ng the tuberculin-induced inflammatory responses in the skin, we have previ ously demonstrated that a therapeutically effective dose of prednisolone su ppressed T-cell, macrophage, and eosinophil infiltration into purified prot ein derivative-induced lesional skin of corticosteroid-sensitive (CS), but not CR, individuals. Objective: Skin biopsy specimens from a tuberculin-induced model of dermal inflammation have been evaluated for the effect of corticosteroids in regul ating components of AP-1 in vivo. Methods: Immunohistochemical analysis of the tuberculin-mediated cutaneous response has been performed on 9 subjects with CS asthma and 6 subjects wit h CR asthma for the regulatory components of AP-1 before and after 9 days o f either 40 mg prednisolone or placebo, Results: Significantly greater expression of c-FOS, phosphorylated c-JUN, a nd phosphorylated JUN N-terminal kinase (JNK) protein has been identified i n CR than in CS subjects. Corticosteroids suppressed phosphorylation of c-J UN and MK in the CS Group (P = .004 for both) but enhanced phosphorylation of c-JUN and JNK in the CR group (P = .031 for both), Conclusion: Resistance to corticosteroids in asthmatic subjects may be caus ed, at least in part, by failure to suppress JNK phosphorylation, leading t o failure to suppress c-JUN N-phosphorylation, Increased JNK may be one of the mechanisms central to the mechanism of CR asthma.