REGULATION OF TRANSFORMING GROWTH FACTOR-β1 AND ITS RECEPTOR BY CYCLOSPORINE IN HUMAN T LYMPHOCYTES

Scarring, fibrosis, and immunosuppression occurs with chronic cyclosporine (CsA) administration. We postulated that CsA may induce transforming growth factor (TGF)-beta 1 secretion from human T lymphocytes, a cytokine with immunoregulatory effects that has been implicated in the pathogenesis of wound healing and 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-dependent manner. Increased TGF-beta 1 secretion in the presence of CsA was accompanied by a 2- to 4-fold increase in TGF-beta 1 mRNA levels due to both enhancement of its nuclear transcription as well as prolongation of TGF-beta 1 mRNA half-life. To determine whether the increase in TGF-beta 1 secretion was also accompanied by a concomitant change in its receptor, TGF-beta 1 receptor expression was analyzed by cross-linking of radioiodinated TGF-beta 1. Unactivated T lymphocytes expressed both a 105-kDa and a 65-kDa TGF-beta receptor. Upon stimulation, a transient increase in receptor density was seen at 12 hr, followed by a decline 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 as the expression of its receptor in activated T lymphocytes. Enhanced TGF-beta 1 production and binding may contribute to the immunosuppressive and fibrosis-promoting effects of CsA therapy.