School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Biochem Pharmacol. 2021 Jan;183:114356. doi: 10.1016/j.bcp.2020.114356. Epub 2020 Dec 4.
Abnormal activation of transforming growth factor (TGF)-β 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)-γ signaling in myofibroblasts was revealed by the decreased expression of phospho-STAT1, IFN-γ-associated genes, and IFN-γ-inducible protein (IP) 10. Microarray analysis showed an induction of fibrotic genes in TGF-β1-differentiated myofibroblasts, whereas IFN-γ-regulated anti-fibrotic genes were suppressed. Interestingly, BIBF 1120 treatment effectively inhibited both STAT3 and SHP2 phosphorylation in TGF-β1-differentiated myofibroblasts and BLM fibrotic lung tissues, which was accompanied by suppression of fibroblast-myofibroblast transition. Moreover, the combined treatment of BIBF 1120 plus IFN-γ or SHP2 inhibitor PHPS1 plus IFN-γ markedly reduced TGF-β1-induced α-smooth muscle actin and further ameliorated BLM lung fibrosis. Accordingly, myofibroblasts were hyporesponsiveness to IFN-γ, while blockade of SHP2 contributed to the anti-fibrotic efficacy of IFN-γ.
转化生长因子 (TGF)-β 的异常激活是成纤维细胞激活和纤维化的常见原因。在博来霉素 (BLM) 诱导的肺纤维化中，磷酸化Src 同源 2 结构域磷酸酶 (SHP) 2、磷酸化信号转导和转录激活因子 (STAT) 3 和细胞因子信号转导抑制剂 (SOCS) 3 的显著表达与肺实质病变和胶原沉积高度相关。人肺成纤维细胞分化为肌成纤维细胞时，SHP2、SOCS3、激活 STAT1 的蛋白抑制剂、STAT3、白细胞介素 (IL)-6 和 IL-10 被激活。肌成纤维细胞中干扰素 (IFN)-γ 信号的显著延迟通过磷酸化 STAT1、IFN-γ 相关基因和 IFN-γ 诱导蛋白 (IP) 10 的表达减少来揭示。微阵列分析显示 TGF-β1 分化的肌成纤维细胞中纤维化基因的诱导，而 IFN-γ 调节的抗纤维化基因受到抑制。有趣的是，BIBF 1120 治疗可有效抑制 TGF-β1 分化的肌成纤维细胞和 BLM 纤维化肺组织中 STAT3 和 SHP2 的磷酸化，同时抑制成纤维细胞-肌成纤维细胞转化。此外，BIBF 1120 联合 IFN-γ 或 SHP2 抑制剂 PHPS1 联合 IFN-γ 的联合治疗显著减少 TGF-β1 诱导的α-平滑肌肌动蛋白，并进一步改善 BLM 肺纤维化。因此，肌成纤维细胞对 IFN-γ 的反应性降低，而阻断 SHP2 有助于 IFN-γ 的抗纤维化作用。
