Hemoglobin Induces the Expression of Indoleamine 2,3-Dioxygenase in Dendritic Cells Through the Activation of PI3K, PKC, and NF-κB and the Generation of Reactive Oxygen Species
Hemoglobin Induces the Expression of Indoleamine 2,3-Dioxygenase in Dendritic Cells Through the Activation of PI3K, PKC, and NF-κB and the Generation of Reactive Oxygen Species
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DOI：
10.1002/jcb.22308
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发表时间：
2009-10-15
影响因子：
4
通讯作者：
Nagase, Fumihiko
中科院分区：
文献类型：
--
作者：
Ogasawara, Nanako;Oguro, Takashi;Nagase, Fumihiko
吲哚胺2，3-双加氧酶（IDO）是色氨酸（Trp）代谢的犬尿氨酸（Kyn）途径中的限速酶。IDO是免疫抑制性的，并且由巨噬细胞和树突状细胞（DC）中的炎症诱导。以往的研究表明，溶血性贫血患者的血清Kyn/Trp水平显着升高。在本研究中，我们证明，血红蛋白（Hb），而不是氯化血红素或血红素的珠蛋白（Apo Hb），诱导IDO表达骨髓来源的髓样树突状细胞（BMDCs）。Hb诱导I κ B α磷酸化和降解。Hb诱导的IDO表达可被PI 3-激酶（PI 3 K）、PKC和核因子（NF）-κ B B抑制剂抑制。Hb将RelA和p52从细胞质易位到细胞核，并诱导细胞内产生活性氧（ROS）。抗氧化剂N-乙酰-L-半胱氨酸（NAC）或SOD与过氧化氢酶的混合物可抑制Hb诱导的IDO表达，而过氧化氢酶抑制剂3-氨基-1，2，4-三氮唑可增强Hb诱导的IDO表达，表明诱导IDO表达需要O-2（-）、H2 O2和羟基自由基等ROS的产生。ROS的产生被PKC抑制剂抑制，并且通过加入PI 3 K抑制剂进一步增强这种作用。Hb诱导Akt磷酸化，其被PI 3 K抑制剂抑制并被PKC抑制剂增强。这些结果表明，NF-κ B B通过PI 3 K-PKC-ROS和PI 3 K-Akt途径的激活是Hb诱导的BMDC中IDO表达所必需的。J.细胞。108：716-725，2009. (C)2009威利-利斯公司
Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism. IDO is immunosuppressive and is induced by inflammation in macrophages and dendritic cells (DCs). Previous studies have shown the serum Kyn/Trp levels in patients with hemolytic anemia to be notably high. In the present study, we demonstrated that hemoglobin (Hb), but not hemin or heme-free globin (Apo Hb), induced IDO expression in bone marrow-derived myeloid DCs (BMDCs). Hb induced the phosphorylation and degradation Of I kappa B alpha. Hb-induced IDO expression was inhibited by inhibitors of PI3-kinase (PI3K), PKC and nuclear factor (NF)-kappa B. Hb translocated both RelA and p52 from the cytosol to the nucleus and induced the intracellular generation of reactive oxygen species (ROS). Hb-induced IDO expression was inhibited by anti-oxidant N-acetyl-L-cysteine (NAC) or mixtures of SOD and catalase, however, IDO expression was enhanced by 3-amino-1,2,4-triazole, an inhibitor of catalase, suggesting that the generation of ROS such as O-2(-), H2O2, and hydroxyl radical is required for the induction of IDO expression. The generation of ROS was inhibited by a PKC inhibitor, and this action was further enhanced by addition of a PI3K inhibitor. Hb induced Akt phosphorylation, which was inhibited by a PI3K inhibitor and enhanced by a PKC inhibitor. These results suggest that the activation of NF-kappa B through the PI3K-PKC-ROS and PI3K-Akt pathways is required for the Hb-induced IDO expression in BMDCs. J. Cell. Biochem. 108: 716-725, 2009. (C) 2009 Wiley-Liss, Inc.