TGF-BETA-1 REGULATES GENE-EXPRESSION OF ITS OWN CONVERTING-ENZYME FURIN

TGF beta 1 is known for its potent and diverse biological effects, inc luding immune regulation, and cell growth and differentiation. We have recently shown that TGF beta 1 precursor is processed by human furin COOH-terminal to the R-H-R-R-278 cleavage site to generate authentic m ature TGF beta 1. In the present study, we demonstrate that steady-sta te furin mRNA levels are increased in rat synovial cells by 2 and 20 n g/ml TGF beta 1. Stimulation with TGF beta 1 results in a significant increase in furin mRNA levels, starting at 3 h with the peak effect ob served at 12 h (2.5-fold increase +/-0.4). TGF beta 1 did not increase furin mRNA stability, and treatment of synovial cells with actinomyci n D, before TGF beta 1 addition prevented the increase in fur gene exp ression, suggesting that the observed regulation occurs at the level o f gene transcription. Treatment of synovial and NRK-49F fibroblastic c ells with exogenous TGF beta 1 (5 ng/ml) or TGF beta 2 (10 ng/ml) tran slates into an increase in pro-TGF beta 1 processing as evidenced by t he appearance of a 40-kD immunoreactive band corresponding to the TGF beta 1 NH2-terminal pro-region. Furin processing activity stimulated b y TGF beta 2 correlates with significant increase in extracellular mat ure and heat-activable TGF beta 1 as determined by an isoform-specific ELISA assay. Taken together, these results demonstrate for the first time that TGF beta 1 upregulates gene expression of its own converting enzyme, and that this expression is translated into augmented process ing of the TGF beta 1 precursor form. Such adaptive responsiveness of the TGF beta 1 convertase may represent an important aspect of TGF bet a 1 bioavailibility in TGF beta 1-related processes and pathological c onditions.