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* Department of Internal Medicine,
Airway Remodeling Laboratory, and
Department of Biochemistry, Chonbuk National University Medical School, Jeonju, South Korea; and
Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
Toluene diisocyanate (TDI)-induced airway disease is a disorder characterized by chronic airway inflammation and airway remodeling. A recently discovered group of cytokines is the IL-17 family, which has been introduced as an important regulator of immune and inflammatory responses, including airway inflammation. Recently, we have reported that phosphatase and tensin homologue deleted on chromosome 10 (PTEN) plays a pivotal role in the pathogenesis of bronchial asthma. However, there are no available data for the effects of PTEN or IL-17 on TDI-induced airway disease and the relationship between PTEN and IL-17. We used a murine model to determine the role of PTEN in the pathogenesis of TDI-induced airway disease and the regulation of IL-17 production. These mice developed the typical pathophysiological features of TDI-induced airway disease and increased IL-17 expression in the lungs. Administration of phosphoinositide 3-kinase inhibitors or adenoviruses carrying PTEN cDNA (AdPTEN) reduced the pathophysiological features of TDI-induced airway disease and decreased the increased levels of IL-17 expression. Our results also showed that PI3K inhibitors or AdPTEN down-regulated a transcription factor, NF-
B activity, and BAY 11-7085 substantially reduced the increased levels of IL-17 after TDI inhalation. We also found that inhibition of IL-17 activity with an anti-IL-17 Ab reduced airway inflammation and airway hyperresponsiveness. These results suggest that PTEN plays a protective role in the pathogenesis of TDI-induced airway disease, at least in part through the regulation of IL-17 expression. Thus, PTEN may be a useful target for treating TDI-induced airway disease by modulating IL-17 expression.
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1 This work was supported by a grant from the Korea Science and Engineering Foundation (KOSEF) through the National Research Laboratory. The program was funded by the Ministry of Science and Technology Grant R0A-2005-000-10052-0 (2007), Korea Research Foundation Grant KRF-2005-201-E00014 funded by the Korean Government (MOEHRD, Basic Research Promotion Fund), Korea Health 21 Research and Development Project Grant A060169 from the Ministry of Health and Welfare, Republic of Korea, and also Korea Health 21 Research and Development Project Grant 0412-CR03-0704-0001).
2 S.R.K. and K.S.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Yong Chul Lee, Department of Internal Medicine, Chonbuk National University Medical School, San 2-20, Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea. E-mail address: leeyc{at}chonbuk.ac.kr
4 Abbreviations used in this paper: TDI, toluene diisocyanate; AdPTEN, adenovirus gene transfer vector expressing PTEN cDNA; BAL, bronchoalveolar lavage; p-Akt, phosphorylated Akt; PAS, periodic acid-Schiff; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homologue deleted on chromosome 10; RL, airway resistance.
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