Immunomodulatory Factors Galectin-9 and Interferon-Gamma Synergize to Induce Expression of Rate-Limiting Enzymes of the Kynurenine Pathway in the Mouse Hippocampus.
Immunomodulatory Factors Galectin-9 and Interferon-Gamma Synergize to Induce Expression of Rate-Limiting Enzymes of the Kynurenine Pathway in the Mouse Hippocampus.
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DOI：
10.3389/fimmu.2016.00422
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发表时间：
2016
影响因子：
7.3
通讯作者：
McCusker RH
中科院分区：
文献类型：
--
作者：
Brooks AK;Lawson MA;Rytych JL;Yu KC;Janda TM;Steelman AJ;McCusker RH
循环促炎细胞因子水平升高与几种精神疾病的病理学相关，特别是重度抑郁症。症状学与犬尿氨酸途径的炎症/马尿氨酸依赖性诱导有关。半乳糖凝集素，如促炎细胞因子，在神经炎症和几种神经系统疾病的发病机制中发挥作用，但没有明确定义的作用机制。它们参与犬尿氨酸途径尚未调查。因此，我们使用体内和离体模型搜索半乳糖凝集素和犬尿氨酸途径之间的联系。给小鼠施用LPS和pI：C以确定在体内炎症激发后半乳糖凝集素（Gal）是否在脑中上调。然后，我们使用器官型海马切片培养物（OHSC）来确定Gal单独或与炎症介质[干扰素-γ（IFNγ）、肿瘤坏死因子-α（TNFα）、白细胞介素-1 β（IL-1β）、多聚肌苷-多聚胞苷酸（pI：C）和地塞米松]联合使用是否能促进海马神经元的增殖。（地塞米松;合成糖皮质激素）]，将增加吲哚胺/色氨酸-2，3-双加氧酶的表达（DO：Ido 1、Ido 2和Tdo 2;犬尿氨酸途径限速酶）。在体内，LPS和pI：C（细菌和病毒模拟物）增加了海马细胞因子（IL-1β、TNFα和IFNγ）、Gal-3和Gal-9以及Ido 1和Ido 2的表达，沿着增加。在体内诱导的细胞因子中，只有IFNγ增加OHSC的两种Ido 1转录物（Ido 1-FL和Ido 1-v1）的表达。尽管单独无效，但Gal-9仅增强IFNγ诱导的Ido 1-FL的表达。类似地，IFNγ诱导几种Ido 2转录物（Ido 2-v1、Ido 2-v3、Ido 2-v4、Ido 2-v5和Ido 2-v6）的表达。Gal-9仅增强IFNγ诱导的Ido 2-v1表达。令人惊讶的是，单独的Gal-9轻微但显著地诱导Tdo 2的表达（Tdo 2-v1和Tdo 2-v2，但不诱导Tdo 2-FL）。这些作用对Gal-9是特异性的，因为Gal-1和Gal-3不改变DO表达。这些结果首次表明，在LPS和pI：C诱导的神经炎症过程中，脑Gal-9增加。Gal-9的表达增加可能对DO表达的神经炎症依赖性诱导至关重要，无论是单独作用（Tdo 2-v1和Tdo 2-v2）还是增强IFNγ活性（Ido 1-FL和Ido 2-v1）。虽然Gal-9的这些新作用是针对海马体描述的，但它们具有在脑外作为DO依赖性免疫调节过程起作用的潜力。随着犬尿氨酸途径激活在多种免疫和精神疾病中的广泛应用，这种协同作用为治疗开发提供了新的靶点。
Elevated levels of circulating pro-inflammatory cytokines are associated with symptomology of several psychiatric disorders, notably major depressive disorder. Symptomology has been linked to inflammation/cytokine-dependent induction of the Kynurenine Pathway. Galectins, like pro-inflammatory cytokines, play a role in neuroinflammation and the pathogenesis of several neurological disorders but without a clearly defined mechanism of action. Their involvement in the Kynurenine Pathway has not been investigated. Thus, we searched for a link between galectins and the Kynurenine Pathway using in vivo and ex vivo models. Mice were administered LPS and pI:C to determine if galectins (Gal’s) were upregulated in the brain following in vivo inflammatory challenges. We then used organotypic hippocampal slice cultures (OHSCs) to determine if Gal’s, alone or with inflammatory mediators [interferon-gamma (IFNγ), tumor necrosis factor-alpha (TNFα), interleukin-1beta (IL-1β), polyinosine-polycytidylic acid (pI:C), and dexamethasone (Dex; synthetic glucocorticoid)], would increase expression of indoleamine/tryptophan-2,3-dioxygenases (DO’s: Ido1, Ido2, and Tdo2; Kynurenine Pathway rate-limiting enzymes). In vivo, hippocampal expression of cytokines (IL-1β, TNFα, and IFNγ), Gal-3, and Gal-9 along with Ido1 and Ido2 were increased by LPS and pI:C (bacterial and viral mimetics). Of the cytokines induced in vivo, only IFNγ increased expression of two Ido1 transcripts (Ido1-FL and Ido1-v1) by OHSCs. Although ineffective alone, Gal-9 accentuated IFNγ-induced expression of only Ido1-FL. Similarly, IFNγ induced expression of several Ido2 transcripts (Ido2-v1, Ido2-v3, Ido2-v4, Ido2-v5, and Ido2-v6). Gal-9 accentuated IFNγ-induced expression of only Ido2-v1. Surprisingly, Gal-9 alone, slightly but significantly, induced expression of Tdo2 (Tdo2-v1 and Tdo2-v2, but not Tdo2-FL). These effects were specific to Gal-9 as Gal-1 and Gal-3 did not alter DO expression. These results are the first to show that brain Gal-9 is increased during LPS- and pI:C-induced neuroinflammation. Increased expression of Gal-9 may be critical for neuroinflammation-dependent induction of DO expression, either acting alone (Tdo2-v1 and Tdo2-v2) or to enhance IFNγ activity (Ido1-FL and Ido2-v1). Although these novel actions of Gal-9 are described for hippocampus, they have the potential to operate as DO-dependent immunomodulatory processes outside the brain. With the expanding implications of Kynurenine Pathway activation across multiple immune and psychiatric disorders, this synergy provides a new target for therapeutic development.
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影响因子：
3.3
作者：
Browne, C. A.;O'Brien, F. E.;Cryan, J. F.
通讯作者：
Cryan, J. F.
影响因子：
3.6
作者：
Kanai M;Funakoshi H;Takahashi H;Hayakawa T;Mizuno S;Matsumoto K;Nakamura T
通讯作者：
Nakamura T
色氨酸代谢的调节，神经发生的促进和色氨酸2,3-二氧酶缺陷型小鼠的焦虑相关行为的改变
DOI：
10.4137/ijtr.s5783
发表时间：
2011-04-11
期刊：
International Journal of Tryptophan Research : IJTR
影响因子：
--
作者：
Funakoshi H;Kanai M;Nakamura T
通讯作者：
Nakamura T
影响因子：
9.3
作者：
Lawson MA;Parrott JM;McCusker RH;Dantzer R;Kelley KW;O'Connor JC
通讯作者：
O'Connor JC
影响因子：
4.4
作者：
Jeon, Sae-Bom;Yoon, Hee Jung;Park, Eun Jung
通讯作者：
Park, Eun Jung