Stimulation of transforming growth factor‐β₁ transcription by cyclosporine

Abstract

In searching for a candidate mechanism for the immunosuppressive as well as fibrogenic consequences of cyclosporine usage, we have explored the hypothesis that cyclosporine stimulates transcription of transforming growth factor-Ol (TGF-/30, a multifunctional cytokine endowed with immunosuppressive and fibrogenic properties. Our results demonstrate that cyclosporine (i) stimulates TGF-I~I promoter-dependent transcription of chloramphenicol acetyl transferase gene in transiently transfected human A-549 cells, (ii) stimulates the synthesis of TGF-O1 RNA transcripts in human T cells, and (iii) permits the expression/emergence of DNA regulatory proteins (retinoblastoma control factor-1 (RCF-1) and RCF-2) that bind and regulate TGF-~I promoter activity. Our studies demonstrate for the first time that cyclosporine stimulates TGF-~I gene transcription and suggest a novel mechanism of action of cyclosporine.

Cyclosporin A inhibits colon cancer cell growth independently of the calcineurin pathway

“…35 Since we have observed an arrest at the G 0 /G 1 stage of cellular proliferation upon treatment with CsA, it is possible that CsA exposure leads to TGFβ production and, consequently, cell cycle arrest of colon adenocarcinoma cells. Even though FK506 is more potent than CsA in inducing TGFβ expression and signaling in rat renal mesangial cells, 36 an important variation among cell lines has been observed, [32][33][34] making it important to test if in our model the cell cycle arrest induced by CsA and not FK506 is mediated by TGFβ. The production of FK506 and looked for NFAT activation.…”

“…Whereas TGFβ treatment may lead to the activation of calcineurin and consequently of NFAT proteins, [29][30][31] in some model systems, treatment with CsA leads to the production of TGFβ. [32][33][34] TGFβ exposure induces an arrest in cell cycle progression of primary endothelial cells while it promotes growth of transformed cells. 35 Since we have observed an arrest at the G 0 /G 1 stage of cellular proliferation upon treatment with CsA, it is possible that CsA exposure leads to TGFβ production and, consequently, cell cycle arrest of colon adenocarcinoma cells.…”

CD4+T cells control the differentiation of Gr1+monocytes into fibrocytes

“…2H). TGF-␤ appeared as possible candidate, because cyclosporine A induces the expression of TGF-␤ from CD4 ϩ T cells (35,36) and TGF-␤ is known to support the generation of fibrocytes (6,15). Blockade of TGF-␤ with an antibody partially reduced the differentiation of monocytes into fibrocytes in the presence of SN CyA whereas it had no effect in the absence of SN CyA (Fig.…”

Connective Tissue Metabolism and Gingival Overgrowth

“…A major and serious side-effect of cyclosporin A therapy is kidney fibrosis, which can result in kidney failure (Myers et al, 1984). Cyclosporin A stimulates levels of circulating TGF-␤ in vivo (Khanna et al, 1997), and enhances TGF-␤ production by renal cells and lymphocytes (Ahuja et al, 1995;Prashar et al, 1995;Young et al, 1995;Wolf et al, 1996). This results in increased collagenous extracellular matrix synthesis and deposition in the glomeruli of the kidney, as demonstrated by studies with anti-TGF-␤1 antibodies that block renal fibrosis and renal dysfunction (Shihab et al, 1996;Islam et al, 2001).…”