Published online before print December 4, 2008

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(American Journal of Pathology. 2009;174:21-33.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080620

Latent Transforming Growth Factor-β-Binding Protein-4 Regulates Transforming Growth Factor-β1 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,^* the BioMatrix Engineering and Regenerative Medicine Center,^¶ and the Departments of Pediatrics (Pulmonary Division), Cell Biology and Pathology, University of Alabama at Birmingham, Birmingham, Alabama; the Departments of Virology and Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland; and the Department of Cell Biology, New York University School of Medicine, New York, New York

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)-β activation, whereas non-fibrogenic Thy-1-expressing [Thy-1 (+)] fibroblasts do not. Activation of latent TGF-β1 by interstitial lung fibroblasts is critical for fibrogenic responses. To better understand the susceptibility of fibrogenic fibroblasts to the stimulation of TGF-β activation, we examined the role of latent TGF-β-binding proteins (LTBPs), key regulators of TGF-β bioavailability and activation, in TGF-β1 activation by these fibroblasts. Treatment of fibroblasts with bleomycin up-regulated LTBP-4 mRNA, protein, and soluble LTBP-4-bound large latent TGF-β1 complexes in Thy-1 (–) fibroblasts to significantly higher levels than in Thy-1 (+) fibroblasts. Bleomycin-induced TGF-β1 activation required LTBP-4, since lung fibroblasts deficient in LTBP-4 did not activate TGF-β1. Expression of LTBP-4 restored TGF-β1 activation in response to bleomycin, but expression either of LTBP-4 lacking the TGF-β-binding site or only the TGF-β-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-β 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-β1 activation in bleomycin-induced lung fibrosis.