Thy-1 Attenuates TNF-α-Activated Gene Expression in Mouse Embryonic Fibroblasts via Src Family Kinase

Thy-1 Attenuates TNF-α-Activated Gene Expression in Mouse Embryonic Fibroblasts via Src Family Kinase

Bin Shan1, James S. Hagood2, Ying Zhuo1, Hong T. Nguyen1, Mark MacEwen2, Gilbert F. Morris3, Joseph A. Lasky1*

1 Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America, 2 Department of Pediatrics, University of Alabama-Birmingham School of Medicine, Birmingham, Alabama, United States of America, 3 Department of Pathology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America

Abstract
Heterogeneous surface expression of Thy-1 in fibroblasts modulates inflammation and may thereby modulate injury and repair. As a paradigm, patients with idiopathic pulmonary fibrosis, a disease with pathologic features of chronic inflammation, demonstrate an absence of Thy-1 immunoreactivity within areas of fibrotic activity (fibroblast foci) in contrast to the predominant Thy-1 expressing fibroblasts in the normal lung. Likewise, Thy-1 deficient mice display more severe lung fibrosis in response to an inflammatory injury than wildtype littermates. We investigated the role of Thy-1 in the response of fibroblasts to the pro-inflammatory cytokine TNF-α. Our study demonstrates distinct profiles of TNF-α-activated gene expression in Thy-1 positive (Thy-1+) and negative (Thy-1−) subsets of mouse embryonic fibroblasts (MEF). TNF-α induced a robust activation of MMP-9, ICAM-1, and the IL-8 promoter driven reporter in Thy-1− MEFs, in contrast to only a modest increase in Thy-1+ counterparts. Consistently, ectopic expression of Thy-1 in Thy-1− MEFs significantly attenuated TNF-α-activated gene expression. Mechanistically, TNF-α activated Src family kinase (SFK) only in Thy-1− MEFs. Blockade of SFK activation abrogated TNF-α-activated gene expression in Thy-1− MEFs, whereas restoration of SFK activation rescued the TNF-α response in Thy-1+ MEFs. Our findings suggest that Thy-1 down-regulates TNF-α-activated gene expression via interfering with SFK- and NF-κB-mediated transactivation. The current study provides a novel mechanistic insight to the distinct roles of fibroblast Thy-1 subsets in inflammation.

Citation: Shan B, Hagood JS, Zhuo Y, Nguyen HT, MacEwen M, et al. (2010) Thy-1 Attenuates TNF-α-Activated Gene Expression in Mouse Embryonic Fibroblasts via Src Family Kinase. PLoS ONE 5(7): e11662. doi:10.1371/journal.pone.0011662

Editor: Toru Ouchi, University of Chicago, United States of America


Received: December 3, 2009; Accepted: June 22, 2010; Published: July 19, 2010

Copyright: © 2010 Shan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was funded by National Institutes of Health (NIH) grants ES010046, HL063778, and HL083480 awarded to J. A. L., and by HL065348, to J.S.H.; B. S. was supported by an NIH postdoctoral training grant T32HL007973. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: jlasky@tulane.edu.

open here to see the full-text:
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0011662