Selective inhibition of inflammatory gene expression in activated T lymphocytes: A mechanism of immune suppression by thiopurines

Carlton W. Thomas, Gennett M. Myhre, Renee Tschumper, Raghavakaimal Sreekumar, Diane F Jelinek, David J. McKean, James J. Lipsky, William J. Sandborn, Laurence J. Egan

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Azathioprine and 6-mercaptopurine are antimetabolite thiopurine drugs that play important roles in the treatment of leukemia and in the management of conditions requiring immunosuppression, such as inflammatory bowel disease. The biochemical pharmacology of these drugs suggests that inhibition of purine nucleotide formation through the 6-thioguanine nucleotide metabolites is their key molecular mechanism. However, it is unclear how these metabolites suppress immunity. We hypothesized that azathioprine produces a selective inhibitory effect on activated but not quiescent T lymphocytes. We first established a model system of T lymphocyte culture with azathioprine that produced pharmacologically relevant concentrations of 6-thioguanine nucleotides. Using genome-wide expression profiling, we identified a group of azathioprine- regulated genes in quiescent and activated T lymphocytes. Several genes involved in immunity and inflammation were selectively down-regulated by azathioprine in stimulated but not quiescent cells. Quantitative reverse transcription- polymerase chain reaction for three of these genes, tumor necrosis factor-related apoptosis-inducing ligand, tumor necrosis factor receptor superfamily member 7, and α4-integrin, confirmed down-regulated expression of transcript levels. Tumor necrosis factor-related apoptosis-inducing ligand protein expression was further studied and found to be inhibited by azathioprine, 6-mercaptopurine, and 6-thioguanine, implying that the inhibitory effects of azathioprine on expression are mediated by 6-thioguanine nucleotides. These results therefore provide a previously unrecognized molecular mechanism for the immunosuppressive properties of thiopurine antimetabolite drugs.

Original languageEnglish (US)
Pages (from-to)537-545
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume312
Issue number2
DOIs
StatePublished - Feb 2005

Fingerprint

Azathioprine
T-Lymphocytes
Gene Expression
Antimetabolites
6-Mercaptopurine
OX40 Receptor
Immunity
Tumor Necrosis Factor-alpha
CD27 Antigens
Pharmaceutical Preparations
Genes
Ligands
Purine Nucleotides
Thioguanine
Apoptosis Regulatory Proteins
Immunosuppressive Agents
Inflammatory Bowel Diseases
Integrins
Immunosuppression
Reverse Transcription

ASJC Scopus subject areas

  • Pharmacology

Cite this

Selective inhibition of inflammatory gene expression in activated T lymphocytes : A mechanism of immune suppression by thiopurines. / Thomas, Carlton W.; Myhre, Gennett M.; Tschumper, Renee; Sreekumar, Raghavakaimal; Jelinek, Diane F; McKean, David J.; Lipsky, James J.; Sandborn, William J.; Egan, Laurence J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 312, No. 2, 02.2005, p. 537-545.

Research output: Contribution to journalArticle

Thomas, Carlton W. ; Myhre, Gennett M. ; Tschumper, Renee ; Sreekumar, Raghavakaimal ; Jelinek, Diane F ; McKean, David J. ; Lipsky, James J. ; Sandborn, William J. ; Egan, Laurence J. / Selective inhibition of inflammatory gene expression in activated T lymphocytes : A mechanism of immune suppression by thiopurines. In: Journal of Pharmacology and Experimental Therapeutics. 2005 ; Vol. 312, No. 2. pp. 537-545.
@article{5dd6114d87864341a9b93a8a2f1fc693,
title = "Selective inhibition of inflammatory gene expression in activated T lymphocytes: A mechanism of immune suppression by thiopurines",
abstract = "Azathioprine and 6-mercaptopurine are antimetabolite thiopurine drugs that play important roles in the treatment of leukemia and in the management of conditions requiring immunosuppression, such as inflammatory bowel disease. The biochemical pharmacology of these drugs suggests that inhibition of purine nucleotide formation through the 6-thioguanine nucleotide metabolites is their key molecular mechanism. However, it is unclear how these metabolites suppress immunity. We hypothesized that azathioprine produces a selective inhibitory effect on activated but not quiescent T lymphocytes. We first established a model system of T lymphocyte culture with azathioprine that produced pharmacologically relevant concentrations of 6-thioguanine nucleotides. Using genome-wide expression profiling, we identified a group of azathioprine- regulated genes in quiescent and activated T lymphocytes. Several genes involved in immunity and inflammation were selectively down-regulated by azathioprine in stimulated but not quiescent cells. Quantitative reverse transcription- polymerase chain reaction for three of these genes, tumor necrosis factor-related apoptosis-inducing ligand, tumor necrosis factor receptor superfamily member 7, and α4-integrin, confirmed down-regulated expression of transcript levels. Tumor necrosis factor-related apoptosis-inducing ligand protein expression was further studied and found to be inhibited by azathioprine, 6-mercaptopurine, and 6-thioguanine, implying that the inhibitory effects of azathioprine on expression are mediated by 6-thioguanine nucleotides. These results therefore provide a previously unrecognized molecular mechanism for the immunosuppressive properties of thiopurine antimetabolite drugs.",
author = "Thomas, {Carlton W.} and Myhre, {Gennett M.} and Renee Tschumper and Raghavakaimal Sreekumar and Jelinek, {Diane F} and McKean, {David J.} and Lipsky, {James J.} and Sandborn, {William J.} and Egan, {Laurence J.}",
year = "2005",
month = "2",
doi = "10.1124/jpet.104.074815",
language = "English (US)",
volume = "312",
pages = "537--545",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Selective inhibition of inflammatory gene expression in activated T lymphocytes

T2 - A mechanism of immune suppression by thiopurines

AU - Thomas, Carlton W.

AU - Myhre, Gennett M.

AU - Tschumper, Renee

AU - Sreekumar, Raghavakaimal

AU - Jelinek, Diane F

AU - McKean, David J.

AU - Lipsky, James J.

AU - Sandborn, William J.

AU - Egan, Laurence J.

PY - 2005/2

Y1 - 2005/2

N2 - Azathioprine and 6-mercaptopurine are antimetabolite thiopurine drugs that play important roles in the treatment of leukemia and in the management of conditions requiring immunosuppression, such as inflammatory bowel disease. The biochemical pharmacology of these drugs suggests that inhibition of purine nucleotide formation through the 6-thioguanine nucleotide metabolites is their key molecular mechanism. However, it is unclear how these metabolites suppress immunity. We hypothesized that azathioprine produces a selective inhibitory effect on activated but not quiescent T lymphocytes. We first established a model system of T lymphocyte culture with azathioprine that produced pharmacologically relevant concentrations of 6-thioguanine nucleotides. Using genome-wide expression profiling, we identified a group of azathioprine- regulated genes in quiescent and activated T lymphocytes. Several genes involved in immunity and inflammation were selectively down-regulated by azathioprine in stimulated but not quiescent cells. Quantitative reverse transcription- polymerase chain reaction for three of these genes, tumor necrosis factor-related apoptosis-inducing ligand, tumor necrosis factor receptor superfamily member 7, and α4-integrin, confirmed down-regulated expression of transcript levels. Tumor necrosis factor-related apoptosis-inducing ligand protein expression was further studied and found to be inhibited by azathioprine, 6-mercaptopurine, and 6-thioguanine, implying that the inhibitory effects of azathioprine on expression are mediated by 6-thioguanine nucleotides. These results therefore provide a previously unrecognized molecular mechanism for the immunosuppressive properties of thiopurine antimetabolite drugs.

AB - Azathioprine and 6-mercaptopurine are antimetabolite thiopurine drugs that play important roles in the treatment of leukemia and in the management of conditions requiring immunosuppression, such as inflammatory bowel disease. The biochemical pharmacology of these drugs suggests that inhibition of purine nucleotide formation through the 6-thioguanine nucleotide metabolites is their key molecular mechanism. However, it is unclear how these metabolites suppress immunity. We hypothesized that azathioprine produces a selective inhibitory effect on activated but not quiescent T lymphocytes. We first established a model system of T lymphocyte culture with azathioprine that produced pharmacologically relevant concentrations of 6-thioguanine nucleotides. Using genome-wide expression profiling, we identified a group of azathioprine- regulated genes in quiescent and activated T lymphocytes. Several genes involved in immunity and inflammation were selectively down-regulated by azathioprine in stimulated but not quiescent cells. Quantitative reverse transcription- polymerase chain reaction for three of these genes, tumor necrosis factor-related apoptosis-inducing ligand, tumor necrosis factor receptor superfamily member 7, and α4-integrin, confirmed down-regulated expression of transcript levels. Tumor necrosis factor-related apoptosis-inducing ligand protein expression was further studied and found to be inhibited by azathioprine, 6-mercaptopurine, and 6-thioguanine, implying that the inhibitory effects of azathioprine on expression are mediated by 6-thioguanine nucleotides. These results therefore provide a previously unrecognized molecular mechanism for the immunosuppressive properties of thiopurine antimetabolite drugs.

UR - http://www.scopus.com/inward/record.url?scp=13244277605&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=13244277605&partnerID=8YFLogxK

U2 - 10.1124/jpet.104.074815

DO - 10.1124/jpet.104.074815

M3 - Article

C2 - 15388785

AN - SCOPUS:13244277605

VL - 312

SP - 537

EP - 545

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -