Cigarette smoke-initiated oxidative stress causes NF-κB activation and lung inflammation via E3 ligase Itch-mediated Txnip degradation

Abstract

Abstract Chronic inflammatory lung diseases including chronic obstructive pulmonary disease (COPD) are characterized by pulmonary structural changes, narrowing of the small airways, and destruction of the lung parenchyma caused by the prolonged inflammation. Sustained inflammation mediated by macrophages is deliberated the critical role in COPD pathogenesis, while inductive mechanisms of the persistent inflammation remain unclear. In this study, we revealed that thioredoxin-interacting protein (Txnip) participated in cigarette smoke-incited NF-κB activation that potentially conducted pulmonary inflammation. Cigarette smoke extract markedly inhibited Txnip expression via an MAPKs-dependent regulation, which accompanied by iNOS/NO and COX-2 induction in RAW264.7 cells. The decreased Txnip was also detected in lung tissues and macrophages obtained from smoking mice, while a higher NF-κB activation and lung inflammation had arisen simultaneously. In addition, cigarette smoke-associated oxidative stress initiated the proteasomal degradation of Txnip followed by the MAPKs-regulated NF-κB activation concurrently. The expression of E3 ligase Itch was elevated in smoking mouse lungs and in hydrogen peroxide-stimulated cells, whereas specific silencing Itch significantly attenuated Txnip degradation as well as NF-κB activation. Moreover, Txnip was distinctly suppressed in lung tissues, bronchoalveolar lavage fluid cells and peripheral blood mononuclear cells obtained from patients with COPD. Accordingly, cigarette smoke-aroused oxidative stress induced Itch-mediated Txnip degradation and further NF-κB inflammation thereby enabling the COPD pathogenesis potentially. MOST 111-2314-B-038-120-MY3 and MOST 111-2320-B-038-012