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J. Biol. Chem., Vol. 276, Issue 20, 17437-17441, May 18, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/20/17437    most recent M100426200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Larios, J. M. Articles by Thannickal, V. J. Search for Related Content PubMed PubMed Citation Articles by Larios, J. M. Articles by Thannickal, V. J. Social Bookmarking                      What's this?

Oxidative Protein Cross-linking Reactions Involving L-Tyrosine in Transforming Growth Factor-1-stimulated Fibroblasts^*

Jose M. Larios, Rohit Budhiraja, Barry L. Fanburg, and Victor J. Thannickal

From the Pulmonary and Critical Care Division, Department of Medicine, New England Medical Center/Tupper Research Institute, Tufts University School of Medicine, Boston, Massachusetts 02111

The mechanisms by which ligand-stimulated generation of reactive oxygen species in nonphagocytic cells mediate biologic effects are largely unknown. The profibrotic cytokine, transforming growth factor-1 (TGF-1), generates extracellular hydrogen peroxide (H₂O₂) in contrast to intracellular reactive oxygen species production by certain mitogenic growth factors in human lung fibroblasts. To determine whether tyrosine residues in fibroblast-derived extracellular matrix (ECM) proteins may be targets of H₂O₂-mediated dityrosine-dependent cross-linking reactions in response to TGF-1, we utilized fluorophore-labeled tyramide, a structurally related phenolic compound that forms dimers with tyrosine, as a probe to detect such reactions under dynamic cell culture conditions. With this approach, a distinct pattern of fluorescent labeling that seems to target ECM proteins preferentially was observed in TGF-1-treated cells but not in control cells. This reaction required the presence of a heme peroxidase and was inhibited by catalase or diphenyliodonium (a flavoenzyme inhibitor), similar to the effect on TGF-1-induced dityrosine formation. Exogenous addition of H₂O₂ to control cells that do not release extracellular H₂O₂ produced a similar fluorescent labeling reaction. These results support the concept that, in the presence of heme peroxidases in vivo, TGF-1-induced H₂O₂ production by fibroblasts may mediate oxidative dityrosine-dependent cross-linking of ECM protein(s). This effect may be important in the pathogenesis of human fibrotic diseases characterized by overexpression/activation of TGF-1.

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