Interferon alpha inhibits antigen-specific production of proinflammatory cytokines and enhances antigen-specific transforming growth factor beta production in antigen-induced arthritis
2013 (English)In: Arthritis Research and Therapy, ISSN 1478-6354, Vol. 15, no 5, R143- p.Article in journal (Refereed) Published
Introduction: Interferon alpha (IFN-Î±) has a complex role in autoimmunity, in that it may both enhance and prevent inflammation. We have previously shown that the presence of IFN-Î± at sensitization protects against subsequent antigen-triggered arthritis. To understand this tolerogenic mechanism, we performed a descriptive, hypothesis-generating study of cellular and humoral responses associated with IFN-Î±-mediated protection against arthritis.Methods: Arthritis was evaluated at day 28 in mice given a subcutaneous injection of methylated bovine serum albumin (mBSA), together with Freund adjuvant and 0 to 5,000 U IFN-Î± at days 1 and 7, followed by intraarticular injection of mBSA alone at day 21. The effect of IFN-Î± on mBSA-specific IgG1, IgG2a, IgG2b, IgA, and IgE was evaluated by enzyme-linked immunosorbent assay (ELISA). Cytokines in circulation and in ex vivo cultures on mBSA restimulation was evaluated with ELISA and Luminex, and the identity of cytokine-producing cells by fluorescence-activated cell sorting (FACS) analysis.Results: Administration of IFN-Î± protected mice from arthritis in a dose-dependent manner but had no effect on antigen-specific antibody levels. However, IFN-Î± did inhibit the initial increase of IL-6, IL-10, IL-12, and TNF, and the recall response induced by intraarticular mBSA challenge of IL-1Î², IL-10, IL-12, TNF, IFN-Î³, and IL-17 in serum. IFN-Î± decreased both macrophage and CD4+ T cell-derived IFN-Î³ production, whereas IL-17 was decreased only in CD4+ T cells. Ex vivo, in mBSA-restimulated spleen and lymph node cell cultures, the inhibitory effect of in vivo administration of IFN-Î± on proinflammatory cytokine production was clearly apparent, but had a time limit. An earlier macrophage-derived, and stronger activation of the antiinflammatory cytokine transforming growth factor beta (TGF-Î²) was observed in IFN-Î±-treated animals, combined with an increase in CD4+ T cells producing TGF-Î² when arthritis was triggered by mBSA (day 21). Presence of IFN-Î± at immunizations also prevented the reduction in TGF-Î² production, which was induced by the intraarticular mBSA injection triggering arthritis in control animals.Conclusions: Administration of IFN-Î± has a profound effect on the cellular response to mBSA plus adjuvant, but does not affect antigen-specific Ig production. By including IFN-Î± at immunizations, spleen and lymph node cells inhibit their repertoire of antigen-induced proinflammatory cytokines while enhancing antiinflammatory TGF-Î² production, first in macrophages, and later also in CD4+ T cells. On intraarticular antigen challenge, this antiinflammatory state is reenforced, manifested as inhibition of proinflammatory recall responses and preservation of TGF-Î² levels. This may explain why IFN-Î± protects against antigen-induced arthritis. Â© 2013 Chalise et al.; licensee BioMed Central Ltd.
Place, publisher, year, edition, pages
London, UK: BioMed Central, 2013. Vol. 15, no 5, R143- p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-102367DOI: 10.1186/ar4326ISI: 000329737400043OAI: oai:DiVA.org:liu-102367DiVA: diva2:677167