Tacrolimus induces increased expression of transforming growth factor-β1 in mammalian lymphoid as well as nonlymphoid cells

Background. We and others have reported that cyclosporine (CsA) induces increased expression of transforming growth factor-beta 1 (TGF-beta 1) in vitro as well as in vivo. In view of similarities between tacrolimus and CsA with respect to immunosuppressive mechanisms, we determined whether tacrolimus, in a fashion similar to CsA, induces TGF-beta 1 hyperexpression in mammalian cells. Methods. We studied the induction of TGF-beta 1 mRNA by tacrolimus using reverse transcription-polymerase chain reaction and Northern blot analysis in normal human T cells and A-549 cells (human lung adenocarcinoma cell line), a cell line used to study the biology of TGF-beta and the induction of TGF-beta 1 by CsA. We also measured the induction of TGF-beta 1 protein by tacrolimus in activated human T cells, peripheral blood mononuclear cells, and A-549 cells, using sandwich enzyme-linked immunosorbent assay. Results. A significant increase in the TGF-beta 1 mRNA expression was observed after treatment of T cells or A-549 cells. Tacrolimus treatment resulted also in heightened production of TGF-beta 1 protein by activated T cells, A-549 cells, or peripheral blood mononuclear cells activated with anti-CDS, phytohemagglutinin, and concanavalin A. Conclusions. Our observations that tacrolimus stimulates TGF-beta 1 hyperexpression in mammalian cells suggest a unifying mechanism for the immunosuppressive as well as nephrotoxic properties of tacrolimus, as the multifunctional TGF-beta 1 is a potent immunosuppressive and fibrogenic cytokine.