Peripheral Blood Mononuclear Cell DNA 6-Thioguanine Metabolite Levels Correlate with Decreased Interferon-γ Production in Patients with Crohn's Disease on AZA Therapy

C. Cuffari, D. Y. Li, J. Mahoney, Y. Barnes, T. M. Bayless

Research output: Contribution to journalArticle

Abstract

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are well known for their lymphocytotoxic and bone marrow suppressive effects in the management of patients with leukemia. Although their immunosuppressive properties are mediated by the active AZA antimetabolite 6-thioguanine (6-TG), its mechanism of action is largely unknown. In IBD, a significant inverse correlation has been shown between erythrocyte 6-TG metabolite levels and disease activity, further supporting the proposed immunosuppressive role for 6-TG. Since leukocytes possess quantitatively different purine metabolic pathways compared to erythrocytes, this study aims to measure lymphocyte DNA 6-TG metabolites and correlate levels with the INF-γ and IL-10 cytokine profile in patients with Crohn's disease (CD). Forty-six adult patients with CD, either naive (17) or on long-term (>4-month) AZA therapy (29), had erythrocyte and lymphocyte DNA 6-TG levels measured by reverse-phase HPLC under UV detection (6-TG, 340 nm). Lymphocyte DNA 6-TG was expressed as picomoles per milligram of DNA. Lymphocyte DNA 6-TG metabolite levels were correlated with INF-γ and IL-10 cytokine profiles using the OptEIA kit (Pharmigen). Lymphocyte DNA 6-TG metabolite levels correlate with erythrocyte 6-TG levels (P < 0.03) but not total patient leukocyte levels. Erythrocyte 6-TG metabolite levels correlated (P < 0.01) inversely with INF-γ but not IL-10 cytokine levels. This study suggests a preferential dampening of the TH1 response on exposure to 6-TG and a possible immunosuppressive mechanism of action for AZA. Future studies are needed to determine if cytokine profiles can be used to predict recalcitrant CD to AZA therapy.

Original languageEnglish (US)
Pages (from-to)133-137
Number of pages5
JournalDigestive diseases and sciences
Volume49
Issue number1
DOIs
StatePublished - Jan 1 2004

Keywords

  • 6-Mercaptopurine
  • Azathioprine
  • Crohn's disease
  • IL-10
  • INF-γ
  • Lymphocyte DNA-6-TG

ASJC Scopus subject areas

  • Physiology
  • Gastroenterology

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