title: IDO1 and TGF-β Mediate Protective Effects of IFN-α in Antigen-Induced Arthritis.
abstract: IFN-α prevents Ag-induced arthritis (AIA), and in this study we investigated the role of IDO1 and TGF-β signaling for this anti-inflammatory property of IFN-α. Arthritis was induced by methylated BSA (mBSA) in mBSA-sensitized wild-type (WT), Ido1-/-, or Ifnar-/-mice, treated or not with IFN-α or the IDO1 product kynurenine (Kyn). Enzymatic IDO1 activity, TGF-β, and plasmacytoid dendritic cells (pDC) were neutralized by 1-methyltryptophan and Abs against TGF-β and pDC, respectively. IDO1 expression was determined by RT-PCR, Western blot, and FACS, and enzymatic activity by HPLC. Proliferation was measured by3H-thymidine incorporation and TGF-β by RT-PCR and ELISA. WT but not Ido1-/-mice were protected from AIA by IFN-α, and Kyn, the main IDO1 product, also prevented AIA, both in WT and Ifnar-/-mice. Protective treatment with IFN-α increased the expression of IDO1 in pDC during AIA, and Ab-mediated depletion of pDC, either during mBSA sensitization or after triggering of arthritis, completely abrogated the protective effect of IFN-α. IFN-α treatment also increased the enzymatic IDO1 activity (Kyn/tryptophan ratio), which in turn activated production of TGF-β. Neutralization of enzymatic IDO1 activity or TGF-β signaling blocked the protective effect of IFN-α against AIA, but only during sensitization and not after triggering of arthritis. Likewise, inhibition of the IDO1 enzymatic activity in the sensitization phase, but not after triggering of arthritis, subdued the IFN-α-induced inhibition of mBSA-induced proliferation. In conclusion, presence of IFN-α at Ag sensitization activates an IDO1/TGF-β-dependent anti-inflammatory program that upon antigenic rechallenge prevents inflammation via pDC.
authors.affiliation: Division of Rheumatology, Autoimmunity, and Immune Regulation, Department of Clinical and Experimental Medicine, Linköping University, Linköping 58185, Sweden; jaya.prakash.chalise@liu.se mattias.magnusson@liu.se.
authors.forename: Jaya Prakash
authors.identifier: 0000-0001-6462-2819
authors.initials: JP
authors.lastname: Chalise
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy.
authors.forename: Maria Teresa
authors.identifier: 0000-0002-0417-1638
authors.initials: MT
authors.lastname: Pallotta
authors.affiliation: Division of Rheumatology, Autoimmunity, and Immune Regulation, Department of Clinical and Experimental Medicine, Linköping University, Linköping 58185, Sweden.
authors.forename: Sudeep Chenna
authors.initials: SC
authors.lastname: Narendra
authors.affiliation: Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping 58185, Sweden; and.
authors.forename: Björn
authors.initials: B
authors.lastname: Carlsson
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy.
authors.forename: Alberta
authors.identifier: 0000-0002-2650-072X
authors.initials: A
authors.lastname: Iacono
authors.affiliation: Division of Rheumatology, Autoimmunity, and Immune Regulation, Department of Clinical and Experimental Medicine, Linköping University, Linköping 58185, Sweden.
authors.forename: Joanitah
authors.initials: J
authors.lastname: Namale
authors.affiliation: EPIRUS Biopharmaceuticals Netherlands BV, 3584 CM Utrecht, the Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy.
authors.forename: Ursula
authors.identifier: 0000-0001-7952-1850
authors.initials: U
authors.lastname: Grohmann
authors.affiliation: Division of Rheumatology, Autoimmunity, and Immune Regulation, Department of Clinical and Experimental Medicine, Linköping University, Linköping 58185, Sweden.
authors.forename: Mattias
authors.identifier: 0000-0002-6565-4027
authors.initials: M
authors.lastname: Magnusson
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007737:Kynurenine / Q000008:administration & dosage; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000276:immunology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C583637:IDO1 protein, mouse; C508032:Ifnar1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016212:Transforming Growth Factor beta; D053633:Receptor, Interferon alpha-beta; D012710:Serum Albumin, Bovine; D007737:Kynurenine