REGULATION OF TRANSFORMING GROWTH FACTOR-BETA(1) AND ITS RECEPTOR BY CYCLOSPORINE IN HUMAN T-LYMPHOCYTES

Scarring, fibrosis, and immunosuppression occurs with chronic cyclospo rine (CsA) administration. We postulated that CsA may induce transform ing growth factor (TGF)-beta(1) secretion from human T lymphocytes, a cytokine with immunoregulatory effects that has beep implicated in the pathogenesis of wound healing ang scarring. TGF-beta(1) was measured in serum-free supernatants harvested from T lymphocytes stimulated in the presence of CsA by a specific sandwich ELISA. CsA (10-1000 ng/ml) enhanced TGF-beta(1) secretion by approximately 40-80% in a dose-depen dent manner. Increased TGF-beta(1) secretion in the presence of CsA wa s accompanied by a 2- to 4-fold increase in TGF-beta(1) mRNA levels du e to both enhancement of its nuclear transcription as well as prolonga tion of TGF-B-1 mRNA half-life, To determine whether the increase in T GF-beta(1) secretion was also accompanied by a concomitant change in i ts receptor, TGF-beta receptor expression was analyzed by cross-linkin g of radioiodinated TGF-beta(1). Unactivated T lymphocytes expressed b oth a 105-kDa and a 65-kDa TGF-beta receptor. Upon stimulation, a tran sient increase in receptor density was seen gt 12 hr, followed by a de cline at later time points. Cells treated with CsA exhibited at least 2-fold higher levels of TGF-beta receptors in a dose-dependent manner, Thus, CsA enhances the production of TGF-beta(1) protein as well gs t he expression of its receptor in activated T lymphocytes. Enhanced TGF -beta(1) production and binding may contribute to the immunosuppressiv e and fibrosis-promoting effects of CsA therapy.