title: Interferon alpha inhibits antigen-specific production of proinflammatory cytokines and enhances antigen-specific transforming growth factor beta production in antigen-induced arthritis.
abstract: BACKGROUND
  Interferon alpha (IFN-α) has a complex role in autoimmunity, in that it may both enhance and prevent inflammation. We have previously shown that the presence of IFN-α 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-α-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-α at days 1 and 7, followed by intraarticular injection of mBSA alone at day 21. The effect of IFN-α 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-α protected mice from arthritis in a dose-dependent manner but had no effect on antigen-specific antibody levels. However, IFN-α 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-1β, IL-10, IL-12, TNF, IFN-γ, and IL-17 in serum. IFN-α decreased both macrophage and CD4+ T cell-derived IFN-γ 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-α 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-β) was observed in IFN-α-treated animals, combined with an increase in CD4+ T cells producing TGF-β when arthritis was triggered by mBSA (day 21). Presence of IFN-α at immunizations also prevented the reduction in TGF-β production, which was induced by the intraarticular mBSA injection triggering arthritis in control animals.
  
  
  CONCLUSIONS
  Administration of IFN-α has a profound effect on the cellular response to mBSA plus adjuvant, but does not affect antigen-specific Ig production. By including IFN-α at immunizations, spleen and lymph node cells inhibit their repertoire of antigen-induced proinflammatory cytokines while enhancing antiinflammatory TGF-β 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-β levels. This may explain why IFN-α protects against antigen-induced arthritis.
authors.forename: Jaya
authors.initials: J
authors.lastname: Chalise
authors.forename: Sudeep
authors.initials: S
authors.lastname: Narendra
authors.forename: Bhesh
authors.initials: B
authors.lastname: Paudyal
authors.forename: Mattias
authors.initials: M
authors.lastname: Magnusson
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood / Q000276:immunology* / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology*; D007270:Injections, Intra-Articular; D016898:Interferon-alpha / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000276:immunology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000097:blood / Q000276:immunology*
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D016898:Interferon-alpha; D016212:Transforming Growth Factor beta; C029180:methylated bovine serum albumin; D012710:Serum Albumin, Bovine; D007073:Immunoglobulin E