TGF beta 1 regulates gene expression of its own converting enzyme furin

TGF beta 1 is known for its potent and diverse biological effects, including 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 mature TGF beta 1. In the present study, we demonstrate that steady-state furin mRNA levels are increased in rat synovial cells by 2 and 20 ng/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 observed at 12 h (2.5-fold increase +/-0.4). TGF beta 1 did not increase furin mRNA stability, and treatment of synovial cells with actinomycin D, before TGF beta 1 addition prevented the increase in fur gene expression, suggesting that the observed regulation occurs at the level of gene transcription. Treatment of synovial and NRK-49F fibroblastic cells with exogenous TGF beta 1 (5 ng/ml) or TGF beta 2 (10 ng/ml) translates into an increase in pro-TGF beta 1 processing as evidenced by the appearance of a 40-kD immunoreactive band corresponding to the TGF beta 1 NH2-terminal pro-region. Furin processing activity stimulated by TGF beta 2 correlates with significant increase in extracellular mature 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 processing of the TGF beta 1 precursor form. Such adaptive responsiveness of the TGF beta 1 convertase may represent an important aspect of TGF beta 1 bioavailibility in TGF beta 1-related processes and pathological conditions.