Abstract
Type I interferons are pleiotropic cytokines having an important regulatory role in autoimmune diseases including rheumatoid arthritis. Our earlier data show that IFN α protects against mBSA induced arthritis (Type I IFN protects against arthritis. Eur J Immunol June 2011;41(6):1687–95) . This IFN α mediated protection was manifested by inhibition of antigen specific proliferation but antigen specific total IgG levels remained largely unaffected. To further define the altered cellular response associated with IFNa-mediated protection against arthritis, the circulating cytokines as well as cytokines produced upon antigen restimulation of leukocytes ex vivo during the development of arthritis (day 14, day 21 and on the day of termination, day 28) was determined. We also assessed the effect of IFN α on antigen-specific IgG isotypes, which may differ depending on the dominant T helper cell response. Arthritis was induced by two injections (day 1 and day 7) of mBSA and adjuvant, with or without 100–5000 U of IFNa. Arthritis was triggered by intra-articular injection of mBSA on day 21 and arthritis was scored on day 28. Presence of IFNaat the time of antigen-sensitization protected mice from arthritis in a dose-dependent manner. No significant differences were found on antigen specific serum IgG1, IgG2a and IgG2b levels regardless of IFN α treatment. The circulating cytokine analysis as measured by Luminex showed that IFN- α decreases the production of cytokines IL-6 and IL-13 in the initial phase (day 14) of arthritis induction. Furthermore, this inhibitory effect of IFNawas also apparent in antigen-specific cytokine release ex-vivo at day 14. In the arthritis phase (day 28), IFN α significantly reduced the levels of circulating, pro-inflammatory cytokines (IL-1 β , IL-17, TNF- α , IFN γ , and IL-12), which were clearly up-regulated in the control group. However, antigen-specific release of cytokines (IFN γ , IL-6, IL-17 and IL-10) after re-stimulation ex-vivo at the day of termination (day 28) showed that splenocytes from IFNatreated mice responded with higher cytokine levels than controls. Conclusion: The ability of IFNato prevent arthritis development is most likely due to its effects on cellular rather than humoral immunity. Presence of IFNaat the time of antigen sensitization (day 1 and day 7) inhibits both in vivo and ex vivo release of pro-inflammatory cytokines throughout the arthritis induction. This results in clearly lower serum concentrations of pro-inflammatory cytokines after intra-articular challenge (day 28) and likely explains the protective effect of IFNa. The inhibition of cytokine release at the time of arthritis manifestation in the IFN α treated group is in line with our earlier published data of inhibited antigen specific re-call responses upon rechallange with mBSA. The increase in ex-vivo release of cytokines from splenocytes at this time point in the IFNa-treated group may indicate that the inhibitory effect on cytokine release by IFNaadministrated on day 1 and day 7 has a time limit.
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