Synergistic effects of ethanol and isopentenyl pyrophosphate on expansion of γδ T cells in synovial fluid from patients with arthritis

PLoS One. 2014 Aug 4;9(8):e103683. doi: 10.1371/journal.pone.0103683. eCollection 2014.


Low to moderate ethanol consumption has been associated with protective effects in autoimmune diseases such as rheumatoid arthritis, RA. An expansion of γδ T cells induced by isopentenyl pyrophosphate, IPP, likewise seems to have a protective role in arthritis. The aim of this project was to test the hypothesis that low doses of ethanol can enhance IPP-induced expansion of synovial fluid γδ T cells from patients with arthritis and may thereby potentially account for the beneficial effects of ethanol on symptoms of the arthritic process. Thus, mononuclear cells from synovial fluid (SF) from 15 patients with arthritis and from peripheral blood (PB) from 15 healthy donors were stimulated with low concentrations of ethanol and IPP for 7 days in vitro. IPP in combination with ethanol 0.015%, 2.5 mM, equivalent to the decrease per hour in blood ethanol concentration due to metabolism, gave a significantly higher fractional expansion of SF γδ T cells compared with IPP alone after 7 days (ratio 10.1+/-4.0, p<0.0008, n = 12) in patients with arthritis. Similar results were obtained for PB γδ T cells from healthy controls (ratio 2.0+/-0.4, p<0.011, n = 15). The augmented expansion of γδ T cells in SF is explained by a higher proliferation (p = 0.0034, n = 11) and an increased survival (p<0.005, n = 11) in SF cultures stimulated with IPP plus ethanol compared to IPP alone. The synergistic effects of IPP and ethanol indicate a possible allosteric effect of ethanol. Similar effects could be seen when stimulating PB with ethanol in presence of risedronate, which has the ability to increase endogenous levels of IPP. We conclude that expansion of γδ T cells by combinatorial drug effects, possibly in fixed-dose combination, FDC, of ethanol in the presence of IPP might give a protective role in diseases such as arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / pathology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Synergism
  • Ethanol / pharmacology*
  • Etidronic Acid / analogs & derivatives
  • Etidronic Acid / pharmacology
  • Etidronic Acid / therapeutic use
  • Female
  • Hemiterpenes / pharmacology*
  • Humans
  • Interferon-gamma / biosynthesis
  • Lymphocyte Activation / drug effects
  • Male
  • Middle Aged
  • Models, Biological
  • Organophosphorus Compounds / pharmacology*
  • Phenotype
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Risedronic Acid
  • Synovial Fluid / cytology*
  • Synovial Fluid / drug effects
  • Synovial Fluid / immunology
  • T-Lymphocyte Subsets / drug effects*


  • Hemiterpenes
  • Organophosphorus Compounds
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Antigen, T-Cell, gamma-delta
  • isopentenyl pyrophosphate
  • Ethanol
  • Interferon-gamma
  • Risedronic Acid
  • Etidronic Acid

Grant support

This study was financed by Börje Dahlin's Foundation and Polysackaridforskning i Uppsala AB. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.