title: IL-13 induces YY1 through the AKT pathway in lung fibroblasts.
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.
authors.affiliation: Department of Medicine, University of Rochester Medical School, Rochester, New York, United States of America.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Pediatrics, University of Rochester; Rochester, New York, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.affiliation: Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, United States of America.
authors.forename: Haodong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, University of Rochester; Rochester, New York, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Dean
authors.affiliation: Department of Allergy and Clinic Immunology, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of medicine, Pulmonary and critical care, University of Alabama, Birmingham, Alabama, United States of America.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Rochester Medical School, Rochester, New York, United States of America; Department of Pediatrics, University of Rochester; Rochester, New York, United States of America.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sime
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D015854:Up-Regulation; D050986:YY1 Transcription Factor / Q000378:metabolism*
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D018793:Interleukin-13; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C494699:Yy1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt