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PLoS One. 2015 Mar 16;10(3):e0119039. doi: 10.1371/journal.pone.0119039. eCollection 2015.

IL-13 induces YY1 through the AKT pathway in lung fibroblasts.

Author information

1
Department of Medicine, University of Rochester Medical School, Rochester, New York, United States of America.
2
Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
3
Department of Pediatrics, University of Rochester; Rochester, New York, United States of America.
4
Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, United States of America.
5
Department of Allergy and Clinic Immunology, Yale University, New Haven, Connecticut, United States of America.
6
Department of medicine, Pulmonary and critical care, University of Alabama, Birmingham, Alabama, United States of America.
7
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.

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.

PMID:
25775215
PMCID:
PMC4361578
DOI:
10.1371/journal.pone.0119039
[Indexed for MEDLINE]
Free PMC Article

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