Yin Yang 1 Is a Novel Regulator of Pulmonary Fibrosis

Abstract

Rationale: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The transcription factor Yin Yang 1 (YY1) plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known. Objectives: To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis. Methods: Lung fibroblasts were cultured with transforming growth factor (TGF)-b or tumor necrosis factor-a. Nuclear factor (NF)-kB, YY1, and a-smooth muscle actin (SMA) were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1 f/f conditional knockout mouse after being exposed to silica or bleomycin. Measurements and Main Results: TGF-b and tumor necrosis factor-a up-regulated YY1 expression in lung fibroblasts. TGF-b-induced YY1 expression was dramatically decreased by an inhibitor of NF-kB, which blocked I-kB degradation. YY1 is significantly overexpressed in both human IPF and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate a-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1 1/2 ) mice were significantly protected from lung fibrosis, which was associated with attenuated a-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1 f/f mice reduced lung fibrosis. Conclusions: YY1 is overexpressed in fibroblasts in both human IPF and murine models in a NF-kB-dependent manner, and YY1 regulates fibrogenesis at least in part by increasing a-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for pulmonary fibrosis.

Update in Diffuse Parenchymal Lung Disease 2011

“…Lin and colleagues demonstrated that the activity of transcription factor Yin Yang 1 (YY1) in fibroblasts promotes fibrogenesis by increasing myofibroblast differentiation and collagen production (46). YY1 is expressed at high levels in fibroblasts from lungs of patients with IPF and in mouse models of lung fibrosis.…”

Protective Effect of Ginsenoside Rg1 on Bleomycin-Induced Pulmonary Fibrosis in Rats: Involvement of Caveolin-1 and TGF-β1 Signal Pathway

“…As two major biomarkers of collagen, Hyp and α-SMA played important roles in deposition and remodeling of ECM. 27,28) Rg1 may exert anti-fibrosis effect through modifying deposition of collagen and ECM in IPF.…”

Transcriptional Regulation of Human Transforming Growth Factor-α in Astrocytes

“…TNF-α–induced activation of YY1 represses Fas expression, indicating that YY1 contributes to TNF-α–induced cell survival (Huerta-Yepez et al, 2006). YY1 expression is markedly increased in idiopathic pulmonary fibrosis and in mouse models of lung fibrosis (Lin et al, 2011). In the CNS, YY1 also plays a critical role in regulating development and function and accordingly, its involvement in neurological diseases has been suggested (He and Casaccia-Bonnefil 2008).…”