Leukotriene C4 induces TGF-beta1 production in airway epithelium via p38 kinase pathway.
Cysteinyl leukotrienes (CysLTs) play an important role in the pathogenesis of airway remodeling. We investigated the interaction between epithelium and CysLTC4, and the contribution of this interaction to airway fibrosis. Human airway epithelial cells were grown on air-liquid interface culture inserts. CysLTC4 was employed to stimulate the cells. Conditioned medium following CysLTC4 stimulation was coincubated with human lung fibroblasts. Our results have demonstrated that CysLTC4 stimulates airway epithelial cells, through a p38 mitogen-activated protein kinase (MAPK) activation mechanism, to produce transforming growth factor beta1 (TGF-beta1), which results in fibroblast proliferation. The selective p38 MAPK inhibitor S203580 successfully inhibits p38 MAPK phosphorylation and subsequent TGF-beta1 production. CysLT1 receptor antagonist montelukast and corticosteroid inhibit TGF-beta1 production at the mRNA and protein levels. When treated with LTC4, the conditioned medium from epithelial cells enhances fibroblast proliferation, this mitogenic effect being attributed to TGF-beta1 and LTC4 remaining in the culture medium. In addition, LTC4 itself acts as a potential growth factor for lung fibroblasts. These data indicate that interactions between LTC4 and airway epithelial cells may contribute to the pathogenesis of airway remodeling. Early intervention to stop these processes may be useful in preventing airway fibrosis in chronic allergic inflammation.
Perng
Diahn-Warng
DW
Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan. dwperng@vghtpe.gov.tw
Wu
Yu-Chung
YC
Chang
Kuo-Ting
KT
Wu
Mo-Tzu
MT
Chiou
Yih-Chy
YC
Su
Kang-Cheng
KC
Perng
Reury-Perng
RP
Lee
Yu-Chin
YC
D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D017077:Culture Media, Conditioned; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017997:Leukotriene C4; D048051:p38 Mitogen-Activated Protein Kinases