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Published ahead of print on May 11, 2006, doi:10.1165/rcmb.2006-0012OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 35, pp. 407-414, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2006-0012OC

Neutrophil-Derived Elastase Induces TGF-beta1 Secretion in Human Airway Smooth Muscle via NF-{kappa}B Pathway

Kang-Yun Lee, Shu-Chuan Ho, Horng-Chyuan Lin, Shu-Min Lin, Chien-Ying Liu, Chien-Da Huang, Chun-Hua Wang, Kian Fan Chung and Han-Pin Kuo

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; and Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom

Correspondence and requests for reprints should be addressed to Professor Han-Pin Kuo, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199 Tun-Hwa N. Rd., Taipei, Taiwan. E-mail: q8828{at}ms11.hinet.net

Neutrophils are infiltrated in airways of individuals with more severe and chronic asthma, with uncertain significance. Airway smooth muscle (ASM), apart from its contractile properties, is critically involved in the pathogenesis of asthma by producing inflammatory mediators. In the present study, we investigated the impact of neutrophil-derived elastase (NE) on ASM in terms of TGF-beta1 release, and we explored the underlying mechanisms. Primary ASM cells were serum starved for 24 h before stimulation with NE (0.01–0.5 µg/ml). TGF-beta1 in supernatant was determined by ELISA and mRNA quantified by real-time RT-QPCR. NF-{kappa}B nuclear translocation and activation was examined by Western blotting and {kappa}B-2 dEGFP reporter gene assay. Association of IL-1 receptor–associated kinase (IRAK) with MyD88 was studied by co-immunoprecipitation and Toll-like receptor 4 (TLR4) determined by FACS scan and Western blotting. We demonstrated that NE enhanced TGF-beta1 release in a time-dependent manner. This induction was inhibited by actinomycin D (5 mM), cycloheximide (5 mM), and NF-{kappa}B inhibitors, including pyrrolidine dithiocarbamate (PDTC, 1 mM), aspirin (2.5 mM), and sodium salyicylate (2.5 mM). Stimulation with NE was rapidly followed by association of IRAK with MyD88, phosphorylation of I{kappa}B{alpha}, and nuclear translocation of p65 with increased transactivation activity. We also found that TLR4 levels were reduced upon NE treatment. These data suggest that NE upregulates TGF-beta1 gene expression and release via My88/IRAK/NF-{kappa}B pathway, possibly through activation of TLR4, and shed light on a potential role of neutrophils in the pathogenesis of asthma.

Key Words: airway smooth muscle • elastase • NF-{kappa}B • TGF-beta1 • Toll-like receptor 4




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