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IDO1 and TGF-? Mediate Protective Effects of IFN-? in Antigen-Induced Arthritis.

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

SUBMITTER: Chalise JP

PROVIDER: S-EPMC5055200 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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IDO1 and TGF-β Mediate Protective Effects of IFN-α in Antigen-Induced Arthritis.

Chalise Jaya Prakash JP Pallotta Maria Teresa MT Narendra Sudeep Chenna SC Carlsson Björn B Iacono Alberta A Namale Joanitah J Boon Louis L Grohmann Ursula U Magnusson Mattias M

Journal of immunology (Baltimore, Md. : 1950) 20160919 8

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<sup>-/-</sup>, or Ifnar<sup>-/-</sup> 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, resp ...[more]

PMID: 27647832

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Project description:BackgroundChlamydia trachomatis infections in women continue to be a major public health concern due to their high prevalence and consequent reproductive morbidities. While antibiotics are usually efficient to clear the Chlamydia, repeat infections are common and may contribute to pathological outcomes. Interferon-gamma (IFN-γ)-mediated immunity has been suggested to be protective against reinfection, and represent an important anti-chlamydial agent, primarily via the induction of indoleamine-2,3 dioxygenase 1 (IDO1) enzyme. IDO1 catalyzes the degradation of tryptophan, which can eliminate C. trachomatis infection in vitro. Here, we sought to measure IDO1 expression levels and related immune markers during different C. trachomatis infection statuses (repeated vs single infection vs post antibiotic treatment), in vitro and in vivo.MethodsIn this study, we measured the expression levels of IDO1 and immune regulatory markers, transforming growth factor β1 (TGF-β1) and forkhead box P3 (FoxP3), in vaginal swab samples of C. trachomatis-infected women, with either single or repeated infection. In addition, we used an in vitro co-culture model of endometrial carcinoma cell-line and peripheral blood mononuclear cells (PBMCs) to measure the same immune markers.ResultsWe found that in women with repeated C. trachomatis infections vaginal IDO1 and TGF-β1 expression levels were significantly increased. Whereas, women who cleared their infection post antibiotic treatment, had increased levels of IDO1 and TGF-β1, as well as FoxP3. Similarly, using the in vitro model, we found significant upregulation of IDO1 and TGF-β1 levels in the co-culture infected with C. trachomatis. Furthermore, we found that in PBMCs infected with C. trachomatis there was a significant upregulation in IDO1 levels, which was independent of IFN-γ. In fact, C. trachomatis infection in PBMCs failed to induce IFN-γ levels in comparison to the uninfected culture.ConclusionsOur data provide evidence for a regulatory immune response comprised of IDO1, TGF-β1 and FoxP3 in women post antibiotic treatment. In this study, we demonstrated a significant increase in IDO1 expression levels in response to C. trachomatis infection, both in vivo and in vitro, without elevated IFN-γ levels. This study implicates IDO1 and TGF-β1 as part of the immune response to repeated C. trachomatis infections, independently of IFN-γ.

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Dataset Information

IDO1 and TGF-? Mediate Protective Effects of IFN-? in Antigen-Induced Arthritis.

Publications

IDO1 and TGF-β Mediate Protective Effects of IFN-α in Antigen-Induced Arthritis.

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