Chalise Jaya Prakash, Pallotta Maria Teresa, Narendra Sudeep Chenna, Carlsson Björn, Iacono Alberta, Namale Joanitah, Boon Louis, Grohmann Ursula, Magnusson Mattias
Division of Rheumatology, Autoimmunity, and Immune Regulation, Department of Clinical and Experimental Medicine, Linköping University, Linköping 58185, Sweden;
Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy.
J Immunol. 2016 Oct 15;197(8):3142-3151. doi: 10.4049/jimmunol.1502125. Epub 2016 Sep 19.
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 by H-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.
干扰素-α可预防抗原诱导的关节炎（AIA），在本研究中，我们探究了吲哚胺2,3-双加氧酶1（IDO1）和转化生长因子-β（TGF-β）信号传导在干扰素-α这种抗炎特性中的作用。在经甲基化牛血清白蛋白（mBSA）致敏的野生型（WT）、Ido1或Ifnar小鼠中，通过mBSA诱导关节炎，分别用或不用干扰素-α或IDO1产物犬尿氨酸（Kyn）进行处理。分别用1-甲基色氨酸和抗TGF-β及浆细胞样树突状细胞（pDC）的抗体中和IDO1酶活性、TGF-β和pDC。通过逆转录聚合酶链反应（RT-PCR）、蛋白质免疫印迹法和荧光激活细胞分选术（FACS）测定IDO1表达，通过高效液相色谱法（HPLC）测定酶活性。通过³H-胸腺嘧啶核苷掺入法测量增殖，通过RT-PCR和酶联免疫吸附测定法（ELISA）测量TGF-β。干扰素-α可保护WT小鼠而非Ido1小鼠免受AIA影响，并且IDO1的主要产物Kyn在WT和Ifnar小鼠中均能预防AIA。在AIA期间，用干扰素-α进行保护性治疗可增加pDC中IDO1的表达，并且在mBSA致敏期间或关节炎触发后，抗体介导的pDC耗竭完全消除了干扰素-α的保护作用。干扰素-α治疗还增加了IDO1酶活性（Kyn/色氨酸比率），这反过来又激活了TGF-β的产生。中和IDO1酶活性或TGF-β信号传导可阻断干扰素-α对AIA的保护作用，但仅在致敏期间有效，而在关节炎触发后无效。同样，在致敏阶段抑制IDO1酶活性可抑制干扰素-α诱导的对mBSA诱导增殖的抑制作用，但在关节炎触发后则无效。总之，在抗原致敏时存在干扰素-α可激活一个依赖IDO1/TGF-β的抗炎程序，该程序在抗原再次攻击时通过pDC预防炎症。
