Related Experiment Videos
Stimulation of transforming growth factor-beta 1 transcription by cyclosporine
Y Prashar1, A Khanna, P Sehajpal
1Rogosin Institute, Department of Transplantation and Extracorporeal Therapy, New York Hospital-Cornell Medical Center, NY 10021.
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-beta 1 (TGF-beta 1), a multifunctional cytokine endowed with immunosuppressive and fibrogenic properties. Our results demonstrate that cyclosporine (i) stimulates TGF-beta 1 promoter-dependent transcription of chloramphenicol acetyl transferase gene in transiently transfected human A-549 cells, (ii) stimulates the synthesis of TGF-beta 1 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-beta 1 promoter activity. Our studies demonstrate for the first time that cyclosporine stimulates TGF-beta 1 gene transcription and suggest a novel mechanism of action of cyclosporine.
Insights
Cyclosporine stimulates the transcription of transforming growth factor-beta 1 (TGF-beta 1), a key cytokine involved in immune suppression and fibrosis. This finding reveals a novel mechanism for cyclosporine
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Cyclosporine is known for its immunosuppressive and fibrogenic effects.
- The precise molecular mechanisms underlying these effects are not fully understood.
- Transforming growth factor-beta 1 (TGF-beta 1) is a cytokine with known immunosuppressive and fibrogenic properties.
Purpose of the Study:
- To investigate the hypothesis that cyclosporine stimulates TGF-beta 1 gene transcription.
- To elucidate a potential mechanism for cyclosporine's immunosuppressive and fibrogenic actions.
Main Methods:
- Transient transfection of human A-549 cells with a TGF-beta 1 promoter-reporter construct (chloramphenicol acetyl transferase gene).
- Analysis of TGF-beta 1 RNA transcript synthesis in human T cells.
- Assessment of DNA regulatory protein expression (retinoblastoma control factor-1 and -2) binding to the TGF-beta 1 promoter.
Main Results:
- Cyclosporine significantly stimulated TGF-beta 1 promoter-dependent transcription.
- Cyclosporine increased the synthesis of TGF-beta 1 RNA transcripts in human T cells.
- Cyclosporine promoted the expression of regulatory proteins (RCF-1 and RCF-2) that modulate TGF-beta 1 promoter activity.
Conclusions:
- Cyclosporine directly stimulates TGF-beta 1 gene transcription.
- This stimulation of TGF-beta 1 represents a novel mechanism of action for cyclosporine.
- The findings provide a molecular basis for cyclosporine's immunosuppressive and fibrogenic effects.