首页|Overcoming interferon (IFN)-gamma resistance ameliorates transforming growth factor (TGF)-beta-mediated lung fibroblast-to-myofibroblast transition and bleomycin-induced pulmonary fibrosis

Overcoming interferon (IFN)-gamma resistance ameliorates transforming growth factor (TGF)-beta-mediated lung fibroblast-to-myofibroblast transition and bleomycin-induced pulmonary fibrosis

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  • NSTL
  • Elsevier
Abnormal activation of transforming growth factor (TGF)-beta is a common cause of fibroblast activation and fibrosis. In bleomycin (BLM)-induced lung fibrosis, the marked expression of phospho-Src homology-2 domain containing phosphatase (SHP) 2, phospho-signal transducer and activator of transcription (STAT) 3, and suppressor of cytokine signaling (SOCS) 3 was highly associated with pulmonary parenchymal lesions and collagen deposition. Human pulmonary fibroblasts differentiated into myofibroblasts exhibited activation of SHP2, SOCS3, protein inhibitor of activated STAT1, STAT3, interleukin (IL)-6, and IL-10. The significant retardation of interferon (IFN)-gamma signaling in myofibroblasts was revealed by the decreased expression of phospho-STAT1, IFN-gamma-associated genes, and IFN-gamma-inducible protein (IP) 10. Microarray analysis showed an induction of fibrotic genes in TGF-beta 1-differentiated myofibroblasts, whereas IFN-gamma-regulated anti-fibrotic genes were suppressed. Interestingly, BIBF 1120 treatment effectively inhibited both STAT3 and SHP2 phosphorylation in TGF-beta 1-differentiated myofibroblasts and BLM fibrotic lung tissues, which was accompanied by suppression of fibroblastmyofibroblast transition. Moreover, the combined treatment of BIBF 1120 plus IFN-gamma or SHP2 inhibitor PHPS1 plus IFN-gamma markedly reduced TGF-beta 1-induced alpha-smooth muscle actin and further ameliorated BLM lung fibrosis. Accordingly, myofibroblasts were hyporesponsiveness to IFN-gamma, while blockade of SHP2 contributed to the anti fibrotic efficacy of IFN-gamma.

TGF-betaMyofibroblastsIFN-gammaSHP2Fibrosis

Chang, Chun-Jung、Lin, Chiou-Feng、Lee, Chih-Hsin、Chuang, Hsiao-Chi、Shih, Fu-Chia、Wan, Shu-Wen、Tai, Chi、Chen, Chia-Ling

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Taipei Med Univ, Sch Resp Therapy, Coll Med, Taipei, Taiwan

Taipei Med Univ, Sch Med, Dept Microbiol & Immunol, Coll Med, Taipei, Taiwan

Taipei Med Univ, Sch Med, Div Pulm Med, Dept Internal Med,Coll Med, Taipei, Taiwan

I Shou Univ, Sch Med Int Students, Coll Med, Kaohsiung, Taiwan

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2021

10.1016/j.bcp.2020.114356

Biochemical Pharmacology

Biochemical Pharmacology

ISTP
ISSN：0006-2952
年,卷(期)：2021.183
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  • 63