IL4 and IL-17A provide a Th2/Th17-polarized inflammatory milieu in favor of TGF-β1 to induce bronchial epithelial-mesenchymal transition (EMT).
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.
Department of Respiratory Medicine, the Second Xiangya Hospital, Central South University, Changsha, China.
Xiaoying
X
Ji
Jinxiu
J
Li
Li
L
Xu
Wenjing
W
Wang
Ming
M
Luo
Shuangling
S
Luo
Libing
L
Ma
Keng
K
Li
Subo
S
Gong
Long
L
He
Zhijun
Z
Zhang
Ping
P
Yang
Zhiguang
Z
Zhou
Xudong
X
Xiang
Cong-Yi
CY
Wang
D056151:Airway Remodeling / Q000502:physiology*; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism*
C508717:IL17A protein, human; D020381:Interleukin-17; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4
ERK1/2; Severe asthma; airway remodeling; chronic inflammatory milieu; epithelial mesenchymal transition (EMT)