scholarly journals Is the Antiproteinuric Effect of Cyclosporine A Independent of Its Immunosuppressive Function in T Cells?

2012 ◽  
Vol 2012 ◽  
pp. 1-6
Author(s):  
Bin Zhang ◽  
Wei Shi
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Cyclosporine A ◽  
Immunosuppressive Effect ◽  
Molecular Event ◽  
Podocyte Injury ◽  
Antiproteinuric Effect ◽  
Nfat Activation ◽  
Per Se ◽  
Transcription Factor Nfat

The antiproteinuric effect of cyclosporine A(CsA) has been believed to result from its immunosuppressive effect on the transcription factor NFAT in T cells. However, current evidences supporting this hypothesis are missing. A recent study showed that CsA has a direct antiproteinuric effect on podocytes, suggesting a novel non-immunosuppressive mechanism for CsA's antiproteinuric effect. Conditional NFATc1 activation in podoyctes per se is sufficient to induce proteinuria in mice, indicating that NFAT activation in podocytes is a critical pathogenic molecular event leading to podocyte injury and proteinuria. Meanwhile, evidence showed that TRPC6-mediated Ca2+influx stimulates NFAT-dependent TRPC6 expression. Altogether, these advances in podocyte research indicate that calcineurin-NFAT signal or calcineurin-synaptopodin axis has a direct proteinuric effect on podocytes which raises the possibility of developing specific antiproteinuric drugs that lack the unwanted effects of calcineurin or NFAT inhibition.

scholarly journals Requirement for Transcription Factor NFAT in Interleukin-2 Expression

1999 ◽  
Vol 19 (3) ◽  
pp. 2300-2307 ◽  
Author(s):  
Chi-Wing Chow ◽  
Mercedes Rincón ◽  
Roger J. Davis
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Transcription Factor ◽  
Nuclear Translocation ◽  
Interleukin 2 ◽  
Inhibitory Effect ◽  
Dominant Negative ◽  
Activated T Cells ◽  
Nfat Activation ◽  
Nfat Transcription Factor

ABSTRACT The nuclear factor of activated T cells (NFAT) transcription factor is implicated in expression of the cytokine interleukin-2 (IL-2). Binding sites for NFAT are located in the IL-2 promoter. Furthermore, pharmacological studies demonstrate that the drug cyclosporin A inhibits both NFAT activation and IL-2 expression. However, targeted disruption of the NFAT1 and NFAT2 genes in mice does not cause decreased IL-2 secretion. The role of NFAT in IL-2 gene expression is therefore unclear. Here we report the construction of a dominant-negative NFAT mutant (dnNFAT) that selectively inhibits NFAT-mediated gene expression. The inhibitory effect of dnNFAT is mediated by suppression of activation-induced nuclear translocation of NFAT. Expression of dnNFAT in cultured T cells caused inhibition of IL-2 promoter activity and decreased expression of IL-2 protein. Similarly, expression of dnNFAT in transgenic mice also caused decreased IL-2 gene expression. These data demonstrate that NFAT is a critical component of the signaling pathway that regulates IL-2 expression.

scholarly journals Hyperglycemia activates the Ca 2+ /calcineurin‐dependent transcription factor NFAT (Nuclear Factor of Activated T‐Cells) in retinal microvessels in vivo

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Anna V. Zetterqvist ◽  
Jenny Nilsson Öhman ◽  
Sergio Frutos Garcia ◽  
Paul G. McGuire ◽  
Laura Gonzalez Bosc ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Transcription Factor Nfat

scholarly journals Regulation of Transcription Factor NFAT by ADP-Ribosylation

2008 ◽  
Vol 28 (9) ◽  
pp. 2860-2871 ◽  
Author(s):  
Opeyemi A. Olabisi ◽  
Noemi Soto-Nieves ◽  
Edward Nieves ◽  
Teddy T. C. Yang ◽  
XiaoYong Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Interleukin 2 ◽  
Regulation Of Transcription ◽  
Dependent Manner ◽  
Immune Functions ◽  
Genetic Ablation ◽  
Adp Ribosylation ◽  
Parp 1 ◽  
Transcription Factor Nfat

ABSTRACT ADP-ribosylation is a reversible posttranslational modification mediated by poly-ADP-ribose polymerase (PARP). The results of recent studies demonstrate that ADP-ribosylation contributes to transcription regulation. Here, we report that transcription factor NFAT binds to and is ADP-ribosylated by PARP-1 in an activation-dependent manner. Mechanistically, ADP-ribosylation increases NFAT DNA binding. Functionally, NFAT-mediated interleukin-2 (IL-2) expression was reduced in T cells upon genetic ablation or pharmacological inhibition of PARP-1. Parp-1 −/− T cells also exhibit reduced expression of other NFAT-dependent cytokines, such as IL-4. Together, these results demonstrate that ADP-ribosylation mediated by PARP-1 provides a molecular switch to positively regulate NFAT-dependent cytokine gene transcription. These results also imply that, similar to the effect of calcineurin inhibition, PARP-1 inhibition may be beneficial in modulating immune functions.

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