Induction of COX-2/PGE2/IL-6 is crucial for cigarette smoke extract-induced airway inflammation: Role of TLR4-dependent NADPH oxidase activation |
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Authors: | Chih-Chung Lin I-Ta Lee Ya-Lin Yang Chiang-Wen Lee Yu Ru Kou Chuen-Mao Yang |
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Affiliation: | 1. I.I. Rabi Scholar Research Program, Columbia College, Columbia University, New York, NY 10027, USA;2. Center for Experimental Therapeutics and Pharmacoinformatics, Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204, USA;1. Department of Physiology and Pharmacology and Health Aging Research Center, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan;2. Heart Failure Center, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan;3. Department of Anesthetics, Chang Gung Memorial Hospital at Linkou and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan |
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Abstract: | Exposure to cigarette smoke extract (CSE) leads to airway and lung inflammation through an oxidant-antioxidant imbalance. Cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) have been shown to play critical roles in respiratory inflammation. Here, we show that COX-2/PGE2/IL-6 induction is dependent on Toll-like receptor 4 (TLR4)/NADPH oxidase signaling in human tracheal smooth muscle cells (HTSMCs). CSE induced COX-2 expression in vitro in HTSMCs and in vivo in the airways of mice. CSE also directly caused an increase in TLR4. Moreover, CSE-regulated COX-2, PGE2, and IL-6 generation was inhibited by pretreatment with TLR4 Ab; inhibitors of c-Src (PP1), NADPH oxidase (diphenylene iodonium chloride and apocynin), p38 MAPK (SB202190), MEK1/2 (U0126), JNK1/2 (SP600125), and NF-κB (helenalin); a ROS scavenger (N-acetyl-l-cysteine); and transfection with siRNA of TLR4, MyD88, TRAF6, Src, p47phox, p38, p42, JNK2, or p65. CSE-induced leukocyte numbers in BAL fluid were also reduced by pretreatment with these inhibitors. Furthermore, CSE induced p47phox translocation and TLR4/MyD88/TRAF6 and c-Src/p47phox complex formation. We found that PGE2 enhanced IL-6 production in HTSMCs and leukocyte count in BAL fluid. In addition, treatment with nicotine could induce COX-2, PGE2, and IL-6 generation in in vivo and in vitro studies. These results demonstrate that CSE-induced ROS generation was mediated through the TLR4/MyD88/TRAF6/c-Src/NADPH oxidase pathway, in turn initiated the activation of MAPKs and NF-κB, and ultimately induced COX-2/PGE2/IL-6-dependent airway inflammation. |
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