Differential involvement of IkB kinases alpha and beta in asthma and COPD

To evaluate the dysregulation of IKKs-driven NF-kB activation in asthma and COPD and to address the different functions of IKKs, we investigated, by Western Blot and Kinase Assay, the expression and the functional activation of IKK? and IKK?, their regulation by CGs, and their involvement in IL-8 synthesis. The study was performed in PBMC isolated from moderate asthmatics (MA), severe uncontrolled asthmatics (SA), healthy smokers (HS), COPD patients, and controls (C). IKK? activity was significantly higher in COPD and HS than in MA, SA and C. IKK? activity was similar in MA, SA, HS and COPD, and higher than in C. In vitro FP treatment (0.01?M) induced inhibition of both IKK? and IKK? activities in PBMC of MA and SA, COPD and HS, although IKK? activity was more sensitive to FP. PBMC of MA, SA, COPD and HS released similar IL-8 amounts. The IL-8 inhibition, induced in vitro by FP, was higher in asthma than in COPD and HS. In addition, PBMC from C were stimulated with TNF? and cigarette smoke extracts (CSE), in the presence or absence of FP and/or GSH, and in the same experimental conditions we evaluated IL-8 release. FP reduced IKK? and IKK? activities in TNF? and CSE-treated PBMC, but the inhibition of IKK? activity was greater than IKK? activity. GSH improved FP down-regulatory effects on IKK? and reduced IL-8 levels, suggesting that IL-8 release and modulation may be associated to a differential IKKs involvement. Based on differential activation of IKK? and IKK? in asthma and COPD our data suggest a different profile in the upstream dysregulation of IKK-driven NF-kB system in both diseases that although regulate an equal pattern of inflammation, including IL-8, may induce different responses to the drugs.