Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)α/βII
Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)α/βII
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DOI：
10.1074/jbc.m611907200
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发表时间：
2007-05-18
影响因子：
4.8
通讯作者：
Duncan, Ian D.
中科院分区：
文献类型：
--
作者：
Nikodemova, Maria;Watters, Jyoti J.;Duncan, Ian D.
实验性变态反应性脑脊髓炎是一种由T细胞介导的自身免疫性疾病，可导致中枢神经系统（CNS）的脱髓鞘、炎症和轴突缺失。小胶质细胞在主要组织相容性复合物II类（MHC II）依赖性抗原呈递和CNS浸润的致脑炎T细胞的再活化中发挥关键作用。米诺环素是一种四环素类抗生素，具有显著的抗炎特性，在实验中用于治疗许多CNS疾病;然而，米诺环素作用的机制仍不清楚。我们发现，米诺环素2周的管理改善了实验性过敏性脑脊髓炎的临床严重程度，部分涉及脊髓中的MHC II蛋白的下调的效果。因此，我们试图阐明米诺环素抑制小胶质细胞MHC II表达的分子机制。虽然复杂，但辅激活因子II类反式激活因子（CIITA）是MHC II表达的关键调节因子。在这里，我们表明，米诺环素抑制干扰素γ（IFN γ）诱导CIITA和MHC II mRNA。然而，有趣的是，它对STAT 1磷酸化或IRF-1表达没有影响，IRF-1是由IFN γ激活的转录因子，并且是CIITA表达所必需的。进一步的实验表明，在PKC α抑制剂Go 6976的存在下，MHC II表达下调。米诺环素抑制IFN γ诱导的PKC α/β II磷酸化以及随后抑制CIITA表达的PKC α/β II和IRF-1的核转位。我们目前的数据描绘了米诺环素作用的分子途径，包括对PKC α/β II和调节关键炎症基因（如MHC II）表达的转录因子的抑制作用。这种基本机制可能是米诺环素在CNS炎症性疾病中的多效性作用的基础。
Experimental allergic encephalomyelitis, an autoimmune disorder mediated by T cells, results in demyelination, inflammation, and axonal loss in the central nervous system (CNS). Microglia play a critical role in major histocompatibility complex class II (MHC II)-dependent antigen presentation and in reactivation of CNS-infiltrated encephalitogenic T cells. Minocycline, a tetracycline antibiotic, has profound anti-inflammatory properties and is experimentally used for treatment of many CNS disorders; however, the mechanisms involved in minocycline effects remain unknown. We show that administration of minocycline for 2 weeks ameliorated clinical severity of experimental allergic encephalomyelitis, an effect that partially involves the down-regulation of MHC II proteins in the spinal cord. Therefore, we sought to elucidate the molecular mechanisms of minocycline inhibitory effects on MHC II expression in microglia. Although complex, the co-activator class II transactivator (CIITA) is a key regulator of MHC II expression. Here we show that minocycline inhibited interferon gamma(IFN gamma)induced CIITA and MHC II mRNA. Interestingly, however, it was without effect on STAT1 phosphorylation or IRF-1 expression, transcription factors that are activated by IFN gamma and necessary for CIITA expression. Further experiments revealed that MHC II expression is down-regulated in the presence of the PKC alpha inhibitor Go6976. Minocycline inhibited IFN gamma- induced PKC alpha/beta II phosphorylation and the nuclear translocation of both PKC alpha/beta II and IRF-1 that subsequently inhibits CIITA expression. Our present data delineate a molecular pathway of minocycline action that includes inhibitory effects on PKC alpha/beta II and transcription factors that regulate the expression of critical inflammatory genes such as MHC II. Such a fundamental mechanism may underlie the pleiotropic effects of minocycline in CNS inflammatory disorders.