Background The cytokine interferon-alpha (IFNa) may induce adaptive-immunity independent arthritis if present in the joint (1) but may in contrast prevent antigen-induced arthritis if activated during immunisations (2). Here we investigate if this is due to tolerance development in terms of antigen-specific proliferation and cytokine release and evaluate the role of the tolerance-inducing enzyme indoleamine 2, 3 dioxygenase (IDO).
Objectives To determine the importance of IDO for the protective effect of IFNa against mBSA-induced arthritis and to determine how presence of IFNa in the sensitization phase of mBSA-induced arthritis affects antigen-specific proliferation and cytokine release.
Methods Arthritis was induced in pre-sensitized animals (mBSA in Freunds adjuvant with or without addition of IFNa on day 0 and day 7) by intra-articular injection of mBSA in the left knee. PBS was injected in the right knee. IDO was inhibited by inserting a 1-methyl tryptophan releasing pellet under the skin at day 0 or day 21. Placebo-pellet were inserted in the control group. Antigen-specific proliferation was determined by radio immunoassay. Levels of different cytokines were determined by Luminex technology.
Results Type I IFN-mediated protection was associated with diminished antigen-specific proliferation during the immunisation course and inhibited increased production of IL-17, TNF, IFN-gamma, IL-12, IL-1b but not IL-6 after intra-articular challenge. Thus IFNa induces a state of tolerance towards the antigen, which may explain its protective effect in mBSA-induced arthritis. An important mediator of immunological tolerance is the enzyme indoleamine 2, 3 dioxygenase. To determine the role of IDO in IFNa-mediated protection against antigen-induced arthritis, the IDO activity was inhibited by 1-methyl tryptophan (1-MT), a specific inhibitor of the IDO-mediated transformation of tryptophan to kynurenine. Presence of 1-MT-releasing tablets under the skin of mice from the first immunization and onwards slightly, but not significantly diminished the protective effect of IFNa. Insertion of 1-MT-releasing pellet at the time of intra-articular challenge had no effect on IFNa-mediated protection. No significant effect of 1-MT on antigen-specific proliferation was observed.
Conclusions Thus mechanisms independent of the enzymatic activity of IDO are responsible for the protective effect of IFNa in mBSA-induced arthritis.
Magnusson, Zare & Tarkowski., Arthritis & Rheum. 2006. Jan;54(1):148-57
Ying, Chalise, Narendra & Magnusson, Eur. J. Immunol., 2011. Jun;41(6):1687-95
Disclosure of Interest None Declared
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