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Amphiregulin Promotes Fibroblast Activation in Pulmonary Fibrosis
Author(s) -
Liu Tianju,
De Los Santos Francina Gonzalez,
Ding Lin,
Wu Zhe,
Phan Sem H
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.50.6
Subject(s) - amphiregulin , fibroblast , pulmonary fibrosis , telomerase , cancer research , fibrosis , biology , immunology , chemistry , growth factor , cell culture , medicine , receptor , biochemistry , gene , genetics
Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in tissue repair and fibrosis by recent studies. Group 2 innate lymphoid cells derived AREG is reported to be important for the epithelial integrity, and involved in repair of airway epithelium following injury. However AREG is essential for pulmonary fibrosis induced by TGFβ overexpression, and its deficiency significantly impairs bleomycin‐induced pulmonary fibrosis. AREG is significantly induced in BLM‐induced fibrotic lung tissues primarily in bone marrow‐derived CD11c + cells that play a significant role in promoting lung fibrosis. Moreover recombinant AREG stimulates mouse lung fibroblast proliferation accompanied by the induction of telomerase reverse transcriptase (TERT) expression. To further elucidate the possible mechanism by which AREG activates fibroblasts during the development of pulmonary fibrosis, its direct role in fibroblast proliferation and motility was investigated. The results showed that AREG significantly increased human lung fibroblast proliferation. The response to AREG was significantly enhanced in the telomerase expressing lung fibroblasts from an IPF patient compared to telomerase negative cells from control subjects. To assess the importance of induced TERT expression in the AREG‐induced cell proliferation, the effect of TERT overexpression was investigated in the human BJ fibroblast cell line. In response to AREG treatment, BJ5ta cells with stably transfected hTERT exhibited significantly greater proliferation relative to control BJ cells. Conversely, significant reduction of AREG‐induced cell proliferation was noted in TERT deficient fibroblasts. Thus induction of TERT by AREG significantly enhanced fibroblast proliferation. Moreover AREG caused significantly increased lung fibroblast motility in an in vitro scratch assay, which was associated with increased expression of α6 integrin. Finally lung α6 integrin mRNA was highly induced in bleomycin‐induced pulmonary fibrosis, which was significantly diminished in AREG deficient mice. Thus AREG‐induced cell motility might be associated with the induction of α6 integrin expression. Taken together, these findings indicated that AREG‐induced fibroblast activation, motility and invasiveness may contribute to the increased number of fibroblasts in pulmonary fibrosis. Support or Funding Information This study is supported by NIH grants HL052285, HL091775 and HL112880.