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Int J Clin Exp Pathol 2013;6(8):1481-1492

Original Article
IL4 and IL-17A provide a Th2/Th17-polarized inflammatory milieu in favor of TGF-β1 to
induce bronchial epithelial-mesenchymal transition (EMT)

Xiaoying Ji, Jinxiu Li, Li Xu, Wenjing Wang, Ming Luo, Shuangling Luo, Libing Ma, Keng Li, Subo Gong, Long He, Zhijun Zhang, Ping Yang,
Zhiguang Zhou, Xudong Xiang, Cong-Yi Wang

Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University, Changsha, China; Department of Respiratory
Medicine, the Affiliated Hospital, Guilin Medical College, Guilin, China; The Center for Biomedical Research, Key Laboratory of Organ
Transplantation, Ministry of Education, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science and
Technology, 1095 Jiefang Ave., Wuhan, 430030, China; The Center for Biotechnology and Genomic Medicine, Georgia Regents University,
1120 15th Street, CA4098, Augusta, GA 30912, USA; Diabetes Center, Second Xiangya Hospital, Central South University, Changsha, China

Received March 25, 2013; Accepted May 16, 2013; Epub July 15, 2013; Published August 1, 2013

Abstract: Severe asthma is a chronic airway disease characterized by the Th2/Th17-polarized inflammation along with permanent airway
remodeling. Despite past extensive studies, the exact role for Th2 and Th17 cytokines in asthmatic pathoetiology, particularly in the
pathogenesis of bronchial epithelial-mesenchymal transition (EMT), is yet to be fully addressed. We herein conducted studies in 16-HBE cells
and demonstrated that Th2-derived IL-4 and Th17-derived IL-17A provide a chronic inflammatory milieu that favors TGF-β1 to induce bronchial
EMT. A synergic action was noted between TGF-β1, IL-4 and IL-17A in terms of induction of EMT. IL-4 and IL-17A synergized with TGF-β1 to
induce epithelial cells re-entering cell cycle, and to promote epithelial to mesenchymal morphological transistion, and by which they enhanced
the capacity of TGF-β1 to suppress E-cadherin expression, and to induce a-SMA expression in epithelial cells. Mechanistic studies revealed
that this synergic action is coordinated by the regulation of ERK1/2 activity. Our results not only provide a novel insight into the understanding of
the mechanisms underlying airway remodeling in asthmatic condition, but also have the potential for developing more effective therapeutic
strategies against severe asthmatics in clinical settings. (IJCEP1303057).

Keywords: Severe asthma, airway remodeling, chronic inflammatory milieu, epithelial mesenchymal transition (EMT), ERK1/2

Address correspondence to: Dr. Jinxiu Li, Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University,
Changsha, China. Fax: 86-731-8529-5555; E-mail: 183572401@qq.com; Dr. Cong-Yi Wang, The Center for Biomedical Research, Key
Laboratory of Organ Transplantation, Ministry of Education, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of
Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China; The Center for Biotechnology and Genomic Medicine, Georgia Regents
University, 1120 15th Street, CA4098, Augusta, GA 30912, USA. Tel: 86-27-8366-3485; E-mail: cwang@gru.edu