Transforming Growth Factor (Tgf)-?? Mimics and Anti-TGF-?? Antibody Abrogates the in Vivo Effects of Cyclosporine

Khanna, Ashwani; Cairns, Victor; Becker, Carl G.; Hosenpud, Jeffrey D.

doi:10.1097/00007890-199903270-00016

Cited by 99 publications

(18 citation statements)

References 51 publications

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“…CsA also has been shown to induce TGF␤1, a cytokine with immuno-modulatory qualities in diverse cells and tissues (33,34). CnA␤ Ϫ/Ϫ mice showed no difference in serum levels of TGF␤1 or in mRNA levels of TGF␤1 from the spleen and thymus, compared with wild-type strain-matched control mice (data not shown).…”

Section: Cna␤mentioning

confidence: 95%

Defective T cell development and function incalcineurinAβ-deficient mice

Bueno

Brandt

Rothenberg

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

172

157

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The calcium-dependent phosphatase calcineurin and its downstream transcriptional effector nuclear factor of activated T cells (NFAT) are important regulators of inducible gene expression in multiple cell types. In T cells, calcineurin-NFAT signaling represents a critical event for mediating cellular activation and the immune response. The widely used immunosuppressant agents cyclosporin and FK506 are thought to antagonize the immune response by directly inhibiting calcineurin-NFAT signal transduction in lymphocytes. To unequivocally establish the importance of calcineurin signaling as a mediator of the immune response, we deleted the gene encoding the predominant calcineurin isoform expressed in lymphocytes, calcineurin A␤ (CnA␤). CnA␤ ؊/؊ mice were viable as adults, but displayed defective T cell development characterized by fewer total CD3 cells and reduced CD4 and CD8 single positive cells. Total peripheral T cell numbers were significantly reduced in CnA␤ ؊/؊ mice and were defective in proliferative capacity and IL-2 production in response to PMA͞ionomycin and T cell receptor cross-linking. CnA␤ ؊/؊ mice also were permissive to allogeneic tumor-cell transplantation in vivo, similar to cyclosporin-treated wild-type mice. A mechanism for the compromised immune response is suggested by the observation that CnA␤ ؊/؊ T cells are defective in stimulation-induced NFATc1, NFATc2, and NFATc3 activation. These results establish a critical role for CnA␤ signaling in regulating T cell development and activation in vivo.

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Section: Cna␤mentioning

confidence: 95%

Defective T cell development and function incalcineurinAβ-deficient mice

Bueno

Brandt

Rothenberg

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

172

157

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“…Different reports suggest that therapy with immunosuppressors can specifically stimulate the transcription of genes that may contribute to the onset of complications arising from therapy. In par-ticular, CSA increases transcription of the transforming growth factor ␤ gene, suggesting that CSA may induce tumors in part due to overexpression of this immunosuppressive cytokine (13,14). The finding that CSA up-regulates gene expression in cells from different tissues irrespective of their activation state suggests that calcineurin may be the ubiquitous target, which could then affect gene expression either negatively or positively.…”

mentioning

confidence: 99%

Characterization of a Gene Encoding Two Isoforms of a Mitochondrial Protein Up-regulated by Cyclosporin A in Activated T Cells

Mascarell

Auger

Alcover

et al. 2004

Journal of Biological Chemistry

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Cyclosporin A (CSA) is an immunosuppressor used in organ transplantation. A recent proteomic analysis has revealed that activation of T cells in the presence of CSA induces the synthesis of hundreds of new proteins. Here we used representational difference analysis to characterize some of the corresponding induced genes. After cDNA bank screening we focused on one of these genes, which we named CSA-conditional, T cell activation-dependent (CSTAD) gene. This gene produces two mRNAs resulting from alternative splicing events. They encode two proteins of 104 and 141 amino acids, CSTADp-S and CSTADp-L, for the short and long forms, respectively. FK506 had the same effect as CSA, whereas rapamycin did not affect the level of CSTAD gene expression, demonstrating that inhibition of the calcineurin activation pathway is involved in CSTAD gene up-regulation. CSA also led to overexpression of CSTAD in mice immunized in the presence of CSA, confirming the in vitro analysis. Microscopic and cytofluorimetric analysis of cells expressing green fluorescent protein-tagged CSTADp-L and CSTADp-S showed that both proteins colocalize with mitochondrial markers and depolarize the mitochondrial transmembrane potential without causing release of cytochrome c, apoptosis, or necrosis. Both CSTADp isoforms are sensitive to proteinase K, implying that they are located in the mitochondrial outer membrane. These data reveal a new mechanism of action for CSA, which involves up-regulation of a gene whose products are sorted to mitochondria and depolarize the mitochondrial membrane.

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“…Our studies also demonstrate that this OPN induction may be dependent on the induction of TGF-β by these immunosuppressive agents. Earlier we have reported on the histopathological changes in CsA-treated animals in a similar model [14]. The strategies limiting increased TGF-β and/or OPN expression may assist in the control of drug-induced nephrotoxicity in transplant patients.…”

Section: Discussionmentioning

confidence: 96%

“…OPN protein was studied using immunohistochemistry as described earlier [14]. Formalin-fixed tissues were paraffin-embedded and sliced into fine sections, deparaffinized in xylene and rehydrated in graded ethanol to PBS.…”

Section: Methodsmentioning

confidence: 99%

“…The long-term treatment of organ transplant patients with immunosuppressive drugs: cyclosporine (CsA) and tacrolimus (TAC) result in nephrotoxicity, leading to chronic rejection [11]. Contrary to the earlier beliefs, both the drugs have similar nephrotoxic effects and we [12,13,14] have demonstrated that these effects are mediated by transforming growth factor (TGF)-β. In this study, we explored the in vitro and in vivo effects of CsA and TAC on the mRNA and protein expression of OPN.…”

Section: Introductionmentioning

confidence: 99%

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Tacrolimus and Cyclosporinein vitro and in vivo Induce Osteopontin mRNA and Protein Expression in Renal Tissues

Khanna¹

2005

Nephron Exp Nephrol

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The mechanism of immunosuppression-linked nephrotoxicity in organ transplantation remains to be solved. Expression of osteopontin (OPN), a multifunctional secreted glycoprotein, has been associated with various forms of renal injuries. In this study, using in vitro and in vivo models, we examined the effects of cyclosporine (CsA) and tacrolimus (TAC) on OPN mRNA and protein expression. We also examined if CsA- and TAC-induced OPN expression is dependent on transforming growth factor (TGF)-β expression. For in vivo experiments mice and rats were injected with CsA (25 mg/kg) and TAC (0.2 mg/kg). For in vitro experiments, human proximal tubular epithelial (PTE) cells were treated with CsA and TAC for 4 h. To study the in vivo effect of TGF-β on OPN mRNA, mice were injected with recombinant TGF-β protein (3 mg/kg). The expression of OPN was also studied in CsA-treated PTE cells with and without anti-TGF-β antibody. At the end of in vitro and in vivo treatments, RNA was isolated from kidney tissue and renal cells reverse transcribed to cDNA and amplified for OPN mRNA. Using immunochemistry and Western blot analysis OPN protein expression was also studied in vivo and in vitro, respectively. Both in vitro and in vivo treatment with CsA and TAC resulted in significantly increased OPN mRNA and protein expression. TGF-β treatment in vivo also resulted in a significantly increased OPN mRNA expression and anti-TGF-β antibody but not the control antibody in vivo in CsA-treated mice, and in vitro in CsA-treated PTE cells inhibited OPN mRNA expression. OPN may contribute to the CsA- and TAC-induced nephrotoxicity in organ transplant recipients and the increased OPN expression might be mediated by TGF-β.

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Transforming Growth Factor (Tgf)-?? Mimics and Anti-TGF-?? Antibody Abrogates the in Vivo Effects of Cyclosporine

Abstract: The study demonstrates the in vivo modulation of the effects of CsA by manipulating TGF-beta levels and suggests that TGF-beta at least in part mediates CsA's beneficial and detrimental effects.

Cited by 99 publications

References 51 publications

Defective T cell development and function incalcineurinAβ-deficient mice

Defective T cell development and function incalcineurinAβ-deficient mice

Characterization of a Gene Encoding Two Isoforms of a Mitochondrial Protein Up-regulated by Cyclosporin A in Activated T Cells

Tacrolimus and Cyclosporinein vitro and in vivo Induce Osteopontin mRNA and Protein Expression in Renal Tissues

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