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The histone deacetylase inhibitors vorinostat and romidepsin downmodulate IL-10 expression in cutaneous T-cell lymphoma cells

The histone deacetylase inhibitors vorinostat and romidepsin downmodulate IL-10 expression in cutaneous T-cell lymphoma cells
The histone deacetylase inhibitors vorinostat and romidepsin downmodulate IL-10 expression in cutaneous T-cell lymphoma cells
BACKGROUND AND PURPOSE: Vorinostat and romidepsin are histone deacetylase inhibitors (HDI), approved for the treatment of cutaneous T-cell lymphoma (CTCL). However, the mechanism(s) by which these drugs exert their anti-cancer effects are not fully understood. Since CTCL is associated with immune dysregulation, we investigated whether these HDI modulated cytokine expression in CTCL cells. EXPERIMENTAL APPROACH: CTCL cell lines and primary CTCL cells were treated in vitro with vorinostat or romidepsin, or with STAT3 pathway inhibitors. Cell cycle parameters and apoptosis were analysed by propidium iodide and annexin V/propidium iodide staining respectively. Cytokine expression was analysed using QRT-PCR and elisa assays. STAT3 expression/phosphorylation and transcriptional activity were analysed using immunoblotting and transfection/reporter assays respectively. KEY RESULTS: Vorinostat and romidepsin strongly down-regulated expression of the immunosuppressive cytokine, interleukin (IL)-10, frequently overexpressed in CTCL, at both the RNA and protein level in CTCL cell lines and at the RNA level in primary CTCL cells. Vorinostat and romidepsin also increased expression of IFNG RNA and decreased expression of IL-2 and IL-4 RNA, although to a lesser extent compared to IL-10. Transient exposure to vorinostat was sufficient to suppress IL-10 secretion but was not sufficient to irreversibly commit cells to undergo cell death. STAT3 pathway inhibitors decreased production of IL-10 and vorinostat/romidepsin partially decreased STAT3-dependent transcription without effects on STAT3 expression or phosphorylation. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that HDI modulate cytokine expression in CTCL cells, potentially via effects on STAT3. Immunomodulation may contribute to the clinical activity of HDI in this disease.
cutaneous T-cell lymphoma, interleukin 10, romidepsin, vorinostat, cytokine, histone deacetylase, STAT3
0007-1188
1590-1602
Tiffon, C. E.
f60bf2d3-bf41-4b58-9a4d-b3e242700039
Adams, J. E.
ac324c90-70a3-4450-8e0a-ce90c15019b0
van der Fits, L.
06509543-719f-417c-99a8-37a307789403
Wen, Shijun
8cdc63b3-e67c-4c03-b281-3639fb3015bd
Townsend, P. A.
61c2084e-4fb2-4e8e-948a-1f51ba438948
Ganesan, A.
62aa5a87-9308-4383-8686-99726b6bcfb9
Hodges, E.
85c114a2-4533-48d7-8a6c-7b82a4138251
Vermeer, M. H.
dfec6641-9fc5-4e31-b6dc-54bfede474b7
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Tiffon, C. E.
f60bf2d3-bf41-4b58-9a4d-b3e242700039
Adams, J. E.
ac324c90-70a3-4450-8e0a-ce90c15019b0
van der Fits, L.
06509543-719f-417c-99a8-37a307789403
Wen, Shijun
8cdc63b3-e67c-4c03-b281-3639fb3015bd
Townsend, P. A.
61c2084e-4fb2-4e8e-948a-1f51ba438948
Ganesan, A.
62aa5a87-9308-4383-8686-99726b6bcfb9
Hodges, E.
85c114a2-4533-48d7-8a6c-7b82a4138251
Vermeer, M. H.
dfec6641-9fc5-4e31-b6dc-54bfede474b7
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394

Tiffon, C. E., Adams, J. E., van der Fits, L., Wen, Shijun, Townsend, P. A., Ganesan, A., Hodges, E., Vermeer, M. H. and Packham, Graham (2011) The histone deacetylase inhibitors vorinostat and romidepsin downmodulate IL-10 expression in cutaneous T-cell lymphoma cells. British Journal of Pharmacology, 162 (7), 1590-1602. (doi:10.1111/(ISSN)1476-5381). (PMID:21198545)

Record type: Article

Abstract

BACKGROUND AND PURPOSE: Vorinostat and romidepsin are histone deacetylase inhibitors (HDI), approved for the treatment of cutaneous T-cell lymphoma (CTCL). However, the mechanism(s) by which these drugs exert their anti-cancer effects are not fully understood. Since CTCL is associated with immune dysregulation, we investigated whether these HDI modulated cytokine expression in CTCL cells. EXPERIMENTAL APPROACH: CTCL cell lines and primary CTCL cells were treated in vitro with vorinostat or romidepsin, or with STAT3 pathway inhibitors. Cell cycle parameters and apoptosis were analysed by propidium iodide and annexin V/propidium iodide staining respectively. Cytokine expression was analysed using QRT-PCR and elisa assays. STAT3 expression/phosphorylation and transcriptional activity were analysed using immunoblotting and transfection/reporter assays respectively. KEY RESULTS: Vorinostat and romidepsin strongly down-regulated expression of the immunosuppressive cytokine, interleukin (IL)-10, frequently overexpressed in CTCL, at both the RNA and protein level in CTCL cell lines and at the RNA level in primary CTCL cells. Vorinostat and romidepsin also increased expression of IFNG RNA and decreased expression of IL-2 and IL-4 RNA, although to a lesser extent compared to IL-10. Transient exposure to vorinostat was sufficient to suppress IL-10 secretion but was not sufficient to irreversibly commit cells to undergo cell death. STAT3 pathway inhibitors decreased production of IL-10 and vorinostat/romidepsin partially decreased STAT3-dependent transcription without effects on STAT3 expression or phosphorylation. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that HDI modulate cytokine expression in CTCL cells, potentially via effects on STAT3. Immunomodulation may contribute to the clinical activity of HDI in this disease.

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More information

Published date: April 2011
Keywords: cutaneous T-cell lymphoma, interleukin 10, romidepsin, vorinostat, cytokine, histone deacetylase, STAT3

Identifiers

Local EPrints ID: 180099
URI: http://eprints.soton.ac.uk/id/eprint/180099
ISSN: 0007-1188
PURE UUID: 9c81634d-8cf7-43f3-9a62-8d4ea37f6d82
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 06 Apr 2011 10:11
Last modified: 15 Mar 2024 03:05

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Contributors

Author: C. E. Tiffon
Author: J. E. Adams
Author: L. van der Fits
Author: Shijun Wen
Author: P. A. Townsend
Author: A. Ganesan
Author: E. Hodges
Author: M. H. Vermeer
Author: Graham Packham ORCID iD

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