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.
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.
Authors: Sheena D Brown; Lou Ann Brown; Susan Stephenson; Jennifer C Dodds; Shaneka L Douglas; Hongyan Qu; Anne M Fitzpatrick Journal: J Allergy Clin Immunol Date: 2015-02-26 Impact factor: 10.793
Authors: Maria E Laucho-Contreras; Francesca Polverino; Kushagra Gupta; Katherine L Taylor; Emer Kelly; Victor Pinto-Plata; Miguel Divo; Naveed Ashfaq; Hans Petersen; Barry Stripp; Aprile L Pilon; Yohannes Tesfaigzi; Bartolome R Celli; Caroline A Owen Journal: Eur Respir J Date: 2015-02-19 Impact factor: 16.671
Authors: Jane E Tully; James D Nolin; Amy S Guala; Sidra M Hoffman; Elle C Roberson; Karolyn G Lahue; Jos van der Velden; Vikas Anathy; Timothy S Blackwell; Yvonne M W Janssen-Heininger Journal: Am J Respir Cell Mol Biol Date: 2012-05-31 Impact factor: 6.914
Authors: Amarjit S Naura; Hogyoung Kim; Jihang Ju; Paulo C Rodriguez; Joaquin Jordan; Andrew D Catling; Bashir M Rezk; Zakaria Y Abd Elmageed; Kusma Pyakurel; Abdelmetalab F Tarhuni; Mohammad Q Abughazleh; Youssef Errami; Mourad Zerfaoui; Augusto C Ochoa; A Hamid Boulares Journal: J Biol Chem Date: 2012-11-26 Impact factor: 5.157
Authors: John A Marwick; Corina Tudor; Nadia Khorasani; Charalambos Michaeloudes; Pankaj K Bhavsar; Kian F Chung Journal: PLoS One Date: 2015-04-23 Impact factor: 3.240