IκB kinase-driven nuclear factor-κB activation in patients with asthma and chronic obstructive pulmonary disease.

BACKGROUND: Nuclear factor-κB (NF-κB) is a transcriptional factor of different inflammatory patterns involved in asthma and chronic obstructive pulmonary disease (COPD) that is tightly controlled by IκB kinase (IKK) complex. OBJECTIVE: We investigated the dysregulation of IKK-driven NF-κB activation in patients with asthma and COPD. METHODS: We assessed IKKα and IKKβ expression and activation, their regulation by glucocorticosteroids, and their involvement in IL-8 synthesis in PBMCs isolated from asthmatic patients, healthy smokers (HSs), patients with COPD, and control subjects. PBMCs from control subjects were stimulated with TNF-α and cigarette smoke extract in the presence or absence of fluticasone propionate (FP), L-glutathione reduced, or both, and IKK activation and IL-8 release were evaluated. RESULTS: IKKα activity was higher in patients with COPD and HSs than in asthmatic patients and control subjects. IKKβ activity was higher in asthmatic patients, HSs, and patients with COPD than in control subjects. In vitro FP treatment induced inhibition of both IKKα and IKKβ activity in PBMCs from asthmatic patients, patients with COPD, and HSs, although IKKβ activity was more sensitive to FP than that of IKKα. FP reduced the IL-8 released from PBMCs of asthmatic patients, patients with COPD, and HSs, although IL-8 inhibition was higher in asthmatic patients than in patients with COPD and HSs. FP reduced IKKα and IKKβ activities in TNF-α and cigarette smoke extract-treated PBMCs, with higher levels of inhibition for IKKβ than IKKα activity. L-glutathione reduced improved the downregulatory effects of FP on IKKα and IL-8 levels. CONCLUSION: Based on differential activation of IKKα and IKKβ, our findings suggest a different profile in the upstream regulation of the IKK-driven NF-κB system in asthmatic patients and patients with COPD. These differences in the regulation of the inflammatory process may explain, at least in part, the different pharmacologic responses in these patients.