The enzyme IDO-1 is involved in the first stage of tryptophan catabolism and has been described in both microbicidal and tolerogenic microenvironments. Previous data from our group have shown that IDO-1 is differentially regulated in the distinctive clinical forms of leprosy. The present study aims to investigate the mechanisms associated with IDO-1 expression and activity in human monocyte-derived dendritic cells (mDCs) after stimulation with irradiated Mycobacterium leprae and its fractions. M. leprae and its fractions induced the expression and activity of IDO-1 in human mDCs. Among the stimuli studied, irradiated M. leprae and its membrane fraction (MLMA) induced the production of proinflammatory cytokines TNF and IL-6 whereas irradiated M. leprae and its cytosol fraction (MLSA) induced an increase in IL-10. We investigated if TLR2 activation was necessary for IDO-1 induction in mDCs. We observed that in cultures treated with a neutralizing anti-TLR2 antibody, there was a decrease in IDO-1 activity and expression induced by M. leprae and MLMA. The same effect was observed when we used a MyD88 inhibitor. Our data demonstrate that coculture of mDCs with autologous lymphocytes induced an increase in regulatory T (Treg) cell frequency in MLSA-stimulated cultures, showing that M. leprae constituents may play opposite roles that may possibly be related to the dubious effect of IDO-1 in the different clinical forms of disease. Our data show that M. leprae and its fractions are able to differentially modulate the activity and functionality of IDO-1 in mDCs by a pathway that involves TLR2, suggesting that this enzyme may play an important role in leprosy immunopathogenesis.

中文翻译：

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麻风分枝杆菌通过 TLR2 诱导 IDO 在单核细胞衍生的树突细胞中诱导耐受性谱

酶 IDO-1 参与色氨酸分解代谢的第一阶段，并已在杀菌和致耐受微环境中进行了描述。我们小组以前的数据表明，IDO-1 在不同的麻风临床形式中受到不同的调节。本研究旨在研究与受辐照的麻风分枝杆菌及其组分刺激后人单核细胞衍生的树突细胞 (mDC) 中 IDO-1 表达和活性相关的机制。M. leprae及其组分在人 mDC 中诱导 IDO-1 的表达和活性。在研究的刺激物中，辐照的麻风支原体及其膜组分 (MLMA) 诱导了促炎细胞因子 TNF 和 IL-6 的产生，而辐照麻风分枝杆菌及其细胞质组分 (MLSA) 诱导 IL-10 增加。我们研究了 TLR2 激活是否是 mDC 中 IDO-1 诱导所必需的。我们观察到，在用中和性抗 TLR2 抗体处理的培养物中，麻风分枝杆菌和 MLMA诱导的 IDO-1 活性和表达降低。当我们使用 MyD88 抑制剂时观察到相同的效果。我们的数据表明，mDC 与自体淋巴细胞的共培养诱导了 MLSA 刺激培养物中调节性 T (Treg) 细胞频率的增加，表明麻风杆菌成分可能起相反的作用，这可能与 IDO-1 的可疑作用有关在不同临床形式的疾病中。我们的数据显示M. leprae 及其组分能够通过涉及 TLR2 的途径差异调节 mDC 中 IDO-1 的活性和功能，表明该酶可能在麻风免疫发病机制中起重要作用。