151. IL-13 Induces YY1 through the AKT Pathway in Lung Fibroblasts
- Author
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Gang Liu, David A. Dean, Zhou Zhu, Hongwei Yao, Patricia J. Sime, Xin Lin, Jia Guo, and Haodong Xu
- Subjects
Science ,Pulmonary Fibrosis ,Mice, Transgenic ,Biology ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Fibrosis ,medicine ,Animals ,Humans ,Phosphorylation ,Fibroblast ,Protein kinase B ,Lung ,PI3K/AKT/mTOR pathway ,YY1 Transcription Factor ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Interleukin-13 ,Transforming growth factor beta ,Fibroblasts ,medicine.disease ,Actins ,3. Good health ,Up-Regulation ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,embryonic structures ,biology.protein ,Cancer research ,Medicine ,Signal transduction ,Myofibroblast ,Proto-Oncogene Proteins c-akt ,Research Article ,Signal Transduction - 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.
- Published
- 2015