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IDO1 and TGF-beta Mediate Protective Effects of IFN-alpha in Antigen-Induced Arthritis
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
University of Perugia, Italy.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
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2016 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 197, no 8, 3142-3151 p.Article in journal (Refereed) Published
Abstract [en]

IFN-alpha prevents Ag-induced arthritis (AIA), and in this study we investigated the role of IDO1 and TGF-beta signaling for this anti-inflammatory property of IFN-alpha. Arthritis was induced by methylated BSA (mBSA) in mBSA-sensitized wild-type (WT), Ido1(-/-), or Ifnar(-/-) mice, treated or not with IFN-alpha or the IDO1 product kynurenine (Kyn). Enzymatic IDO1 activity, TGF-beta, and plasmacytoid dendritic cells (pDC) were neutralized by 1-methyltryptophan and Abs against TGF-beta and pDC, respectively. IDO1 expression was determined by RT-PCR, Western blot, and FACS, and enzymatic activity by HPLC. Proliferation was measured by H-3-thymidine incorporation and TGF-beta by RT-PCR and ELISA. WT but not Ido1(-/-) mice were protected from AIA by IFN-alpha, and Kyn, the main IDO1 product, also prevented AIA, both in WTand Ifnar(-/-) mice. Protective treatment with IFN-alpha 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-alpha. IFN-alpha treatment also increased the enzymatic IDO1 activity (Kyn/tryptophan ratio), which in turn activated production of TGF-beta. Neutralization of enzymatic IDO1 activity or TGF-beta signaling blocked the protective effect of IFN-alpha 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-alpha-induced inhibition of mBSA-induced proliferation. In conclusion, presence of IFN-alpha at Ag sensitization activates an IDO1/TGF-beta-dependent anti-inflammatory program that upon antigenic rechallenge prevents inflammation via pDC.

Place, publisher, year, edition, pages
AMER ASSOC IMMUNOLOGISTS , 2016. Vol. 197, no 8, 3142-3151 p.
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-133121DOI: 10.4049/jimmunol.1502125ISI: 000387965100018PubMedID: 27647832OAI: oai:DiVA.org:liu-133121DiVA: diva2:1055253
Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2017-04-24
In thesis
1. Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine
Open this publication in new window or tab >>Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, we have studied the immunological processes of joint inflammation that may be targets for future treatment of patients with arthritis. We focus on the immune-modulating properties of interferon-α (IFN-α) and uridine in experimental arthritis. The nucleoside uridine, which is regarded a safe treatment has anti-inflammatory properties notably by inhibiting tumor necrosis factor (TNF) release. Because the inflamed synovium in rheumatoid arthritis (RA) is characterised by pathogenic TNF-production, uridine could potentially be away to ameliorate arthritis. Systemic administration of uridine had no effect on antigeninduced arthritis (AIA), which is a T-cell dependent model where animals are immunized twice (sensitization) with bovine serum albumin (mBSA), before local triggering of arthritis by intra-articular antigen (mBSA) re-challenge. In contrast, intra-articular administration of uridine clearly down modulated development of AIA in a dose dependent manner and inhibited the expression of synovial adhesion molecules, influx of inflammatory leukocytes and synovial expression of TNF and interleukin 6, but did not affect systemic levels of proinflammatory cytokines or antigen-specific T-cell responses. Local administration of uridine may thus be a viable therapeutic option for treatment of arthritis in the future.

Viral double-stranded deoxyribonucleic acid (dsRNA), a common nucleic acid found in most viruses, can be found in the joints of RA patients and local deposition of such viral dsRNA induces arthritis by activating IFN-α. Here we show that arthritis induced by dsRNA can be mediated by IFN-producing dendritic cells in the joint and this may thus explain why viral infections are sometimes associated with arthritis.

Earlier, to study the effect of dsRNA and IFN-α in an arthritis model, that like RA, is dependent on adaptive immunity, dsRNA and IFN-α were administered individually during the development of AIA. Both molecules clearly protected against AIA in a type I IFN receptor-dependent manner but were only effective if administered in the sensitization phase of AIA. Here we show that the anti-inflammatory effect of IFN-α is critically dependent on signalling via transforming growth factor β (TGF-β) and the enzymatic activity of indoleamine 2,3 dioxygenase 1 (IDO). The IDO enzyme is produced by plasmacytoid DC and this cell type was critically required both during antigen sensitization and in the arthritis phase of AIA for the protective effect of IFN-α against AIA. In contrast, TGF-β and the enzymatic activity of IDO were only required during sensitization, which indicate that they are involved in initial steps of tolerogenic antigen sensitization. In this scenario, IFN- α first activates the enzymatic activity of IDO in pDC, which converts Tryptophan to Kynurenine, which thereafter activates TGF-β. Common for IDO-expressing pDC, Kyn and TGF-β is their ability to induce development of regulatory T cells (Tregs). We found that Tregs were crucial for IFN-α-mediated protection against AIA, but only in the arthritis phase. In line with this, adoptive transfer of Tregs isolated from IFN-α treated mice to recipient animals in the arthritis phase clearly protected against AIA. The numbers of Tregs were not significantly altered by IFN-α but IFN-α increased the suppressive capacity of Tregs against antigen-induced proliferation. This enhanced suppressive activity of Tregs in the arthritis phase was dependent on the earlier activated enzyme IDO1 during the sensitization phase of AIA. Thus, presence of IFN-α at the time of antigen sensitization activates the enzymatic activity of IDO, which generates Tregs with enhanced suppressive capacity that upon antigen re-challenge prevents inflammation. We have thus identified one example of how immune tolerance can be developed, that may be a future way to combat autoimmunity.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. 75 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1572
National Category
Immunology in the medical area Pharmacology and Toxicology Microbiology in the medical area Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-136238 (URN)10.3384/diss.diva-136238 (DOI)9789176855416 (ISBN)
Public defence
2017-05-04, Belladonna, Hus 511, Campus US, Linköping, 09:00 (English)
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Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2017-04-11Bibliographically approved

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