Abstract
A key feature of lung fibrosis is the accumulation of myofibroblasts. Interleukin 13 (IL-13) is a pro-fibrotic mediator that directly and indirectly influences the activation of myofibroblasts. Transforming growth factor beta (TGF-β) promotes the differentiation of fibroblasts into myofibroblasts, and can be regulated by IL-13. However, IL-13’s downstream signaling pathways are not completely understood. We previously reported that the transcription factor Yin Yang 1 (YY1) is upregulated in fibroblasts treated with TGF-β and in the lungs of mice and patients with pulmonary fibrosis. Moreover, YY1 directly regulates collagen and alpha smooth muscle actin (α-SMA) expression in fibroblasts. However, it is not known if IL-13 regulates fibroblast activation through YY1 expression. We hypothesize that IL-13 up-regulates YY1 expression through regulation of AKT activation, leading to fibroblast activation. In this study we found that YY1 was upregulated by IL-13 in lung fibroblasts in a dose- and time-dependent manner, resulting in increased α-SMA. Conversely, knockdown of YY1 blocked IL-13-induced α-SMA expression in fibroblasts. Furthermore, AKT phosphorylation was increased in fibroblasts treated with IL-13, and AKT overexpression upregulated YY1, whereas blockade of AKT phosphorylation suppressed the induction of YY1 by IL-13 in vitro. In vivo YY1 was upregulated in fibrotic lungs from CC10-IL-13 transgenic mice compared to that from wild-type littermates, which was associated with increased AKT phosphorylation. Taken together, these findings demonstrate that IL-13 is a potent stimulator and activator of fibroblasts, at least in part, through AKT-mediated YY1 activation.
Highlights
Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation and activation of fibroblasts and myofibroblasts, deposition of extracellular matrix (ECM) proteins, such as collagen, as well as distortion of normal tissue architecture [1]
We found that the levels of Yin Yang 1 (YY1), α-smooth muscle actin (α-SMA) and p-AKT were up-regulated in a time-dependent manner in Interleukin 13 (IL-13)-treated MRC5 as determined by Western blot (Fig. 1A)
We found that IL-13 treatment significantly upregulated YY1 promoter reporter activity in lung fibroblasts (Fig. 1F)
Summary
Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation and activation of fibroblasts and myofibroblasts, deposition of extracellular matrix (ECM) proteins, such as collagen, as well as distortion of normal tissue architecture [1]. Myofibroblasts, derived from fibroblasts via the activity of TGF-β and other stimuli [3], are recognized as major effector cells in pulmonary fibrosis They are characterized by the increased expression of α-smooth muscle actin (α-SMA), enhanced proliferation [4] and resistance to apoptosis[5]. TGF-β is able to activate pro-survival signaling pathways involving AKT and FAK to induce an apoptosis-resistant myofibroblast phenotype [21]. It is not known whether PI3K/AKT signaling is involved in IL-13-induced lung fibrosis. Targeting these pro-survival signaling pathways may provide an effective strategy to control fibroblast accumulation in the years ahead [24,25,26]
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