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J Biol Chem, Vol. 273, Issue 36, 23611-23615, September 4, 1998

Tyrosine Phosphorylation Regulates H₂O₂ Production in Lung Fibroblasts Stimulated by Transforming Growth Factor 1

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

Transforming growth factor 1 (TGF-1) is a multifunctional, profibrotic cytokine involved in cellular growth and differentiation. We have previously described a cell surface-associated H₂O₂-generating NADH:flavin:O₂ oxidoreductase (referred to as NADH oxidase) activity in human lung fibroblasts induced by TGF-1 (Thannickal, V. J., and Fanburg, B. L. (1995) J. Biol. Chem. 270, 30334-30338). In this study, the potential for regulation of this novel TGF-1-activated oxidase in fibroblasts by protein tyrosine phosphorylation was examined. Immunoblots using anti-phosphotyrosine antibody demonstrated a time-dependent but delayed phosphorylation of two proteins of 115 and 103 kDa in cells stimulated with TGF-1 (2 ng/ml). Similar to the effect on TGF-1-induced H₂O₂ production, phosphorylation of these proteins was blocked by the addition of actinomycin D. The protein-tyrosine kinase inhibitors genistein and herbimycin A inhibited TGF-1-induced protein tyrosine phosphorylation, NADH oxidase activation, and H₂O₂ production in a dose-dependent manner. Catalase, diphenyliodonium (an inhibitor of flavoenzymes), and suramin (an inhibitor of receptor activation, added 4 h after TGF-1) had no effect on the induction of protein tyrosine phosphorylation. Phosphorylation of the 115- and 103-kDa proteins preceded the generation of H₂O₂ production and returned to control levels when H₂O₂ was undetectable at 48 h after TGF-1 exposure. These results suggest that protein tyrosine phosphorylation by a nonreceptor protein-tyrosine kinase(s) regulates the activity of the TGF-1-responsive H₂O₂-generating NADH oxidase in human lung fibroblasts. Additionally, this study demonstrates that TGF-1, which binds to a serine-threonine kinase receptor, is able to induce protein tyrosine phosphorylation in a delayed manner via a signaling pathway that requires transcriptional activation.

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