Published online before print December 4, 2008

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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.080620

Accepted for publication October 7, 2008.

Article

Latent Transforming Growth Factor--binding Protein-4 Regulates Transforming Growth Factor-1 Bioavailability for Activation by Fibrogenic Lung Fibroblasts in Response to Bleomycin

Yong Zhou^*, Katri Koli, James S. Hagood, Mi Miao^*, Mahendra Mavalli^*, Daniel B. Rifkin, and Joanne E. Murphy-Ullrich^*¶@

From the Department of Pathology, Division of Molecular and Cellular Pathology,* BioMatrix Engineering and Regenerative Medicine Center,^¶ Departments of Pediatrics (Pulmonary Division), Cell Biology and Pathology, University of Alabama at Birmingham, Birmingham, Alabama; Departments of Virology and Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland; Department of Cell Biology, New York University School of Medicine, New York, New York

^@ To whom correspondence should be addressed. E-mail: murphy{at}uab.edu.

	Abstract

Recent evidence suggests that subsets of lung fibroblasts differentially contribute to fibrogenic progression. We have previously shown that a subset of rat lung fibroblasts with fibrogenic characteristics [Thy-1 (-) fibroblasts] responds to stimuli (bleomycin, interleukin-4, etc) with increased latent transforming growth factor (TGF)- activation, whereas non-fibrogenic Thy-1-expressing [Thy-1 (+)] fibroblasts do not. Activation of latent TGF-1 by interstitial lung fibroblasts is critical for fibrogenic responses. To better understand the susceptibility of fibrogenic fibroblasts to the stimulation of TGF- activation, we examined the role of latent TGF--binding proteins (LTBPs), key regulators of TGF- bioavailability and activation, in TGF-1 activation by these fibroblasts. Treatment of fibroblasts with bleomycin up-regulated LTBP-4 mRNA, protein, and soluble LTBP-4-bound large latent TGF-1 complexes in Thy-1 (-) fibroblasts to significantly higher levels than in Thy-1 (+) fibroblasts. Bleomycin-induced TGF-1 activation required LTBP-4, since lung fibroblasts deficient in LTBP-4 did not activate TGF-1. Expression of LTBP-4 restored TGF-1 activation in response to bleomycin, but expression either of LTBP-4 lacking the TGF--binding site or only the TGF--binding domain did not. Bleomycin treatment of mice increased LTBP-4 expression in the lung. Thy-1 knockout mice had increased levels of both LTBP-4 expression and TGF- activation, as well as enhanced Smad3 phosphorylation compared with wild-type mice. Together, these data identify a critical role for LTBP-4 in the regulation of latent TGF-1 activation in bleomycin-induced lung fibrosis.