Tacrolimus induces increased expression of transforming growth factor-beta1 in mammalian lymphoid as well as nonlymphoid cells

Abstract

Background: We and others have reported that cyclosporine (CsA) induces increased expression of transforming growth factor-beta1 (TGF-beta1) 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-beta1 hyperexpression in mammalian cells.

Methods: We studied the induction of TGF-beta1 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-beta1 by CsA. We also measured the induction of TGF-beta1 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-beta1 mRNA expression was observed after treatment of T cells or A-549 cells. Tacrolimus treatment resulted also in heightened production of TGF-beta1 protein by activated T cells, A-549 cells, or peripheral blood mononuclear cells activated with anti-CD3, phytohemagglutinin, and concanavalin A.

Conclusions: Our observations that tacrolimus stimulates TGF-beta1 hyperexpression in mammalian cells suggest a unifying mechanism for the immunosuppressive as well as nephrotoxic properties of tacrolimus, as the multifunctional TGF-beta1 is a potent immunosuppressive and fibrogenic cytokine.