Histamine Induces Upregulated Expression of Histamine Receptors and Increases Release of Inflammatory Mediators from Microglia
Histamine Induces Upregulated Expression of Histamine Receptors and Increases Release of Inflammatory Mediators from Microglia
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组胺诱导组胺受体表达上调并增加小胶质细胞炎症介质的释放
DOI：
10.1007/s12035-014-8697-6
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发表时间：
2014-06-01
影响因子：
5.1
通讯作者：
Zhang, Shu
中科院分区：
文献类型：
--
作者：
Dong, Hongquan;Zhang, Wei;Zhang, Shu
组胺是一种有效的炎症介质和先天性和适应性免疫反应的调节剂。然而，组胺对小胶质细胞（大脑中的常驻免疫细胞）的影响仍未得到研究。在本研究中，我们发现，小胶质细胞可以组成性表达所有四种组胺受体（H1 R，H2 R，H3 R，和H4 R），和H1 R和H4 R的表达可以选择性地上调在原代培养的小胶质细胞在剂量依赖性的方式由组胺。组胺也可以剂量依赖性地刺激小胶质细胞活化，随后产生促炎因子肿瘤坏死因子（TNF）-α和白细胞介素-6（IL-6）。H1 R和H4 R的拮抗剂而不是H2 R和H3 R的拮抗剂减少组胺诱导的TNF-α和IL-6的产生，MAPK和PI 3 K/AKT通路的激活，以及小胶质细胞中的线粒体膜电位损失，表明组胺的作用是通过H1 R和H4 R。另一方面，JNK、p38或PI 3 K的抑制剂抑制组胺诱导的TNF-α和IL-6从小胶质细胞释放。组胺还激活NF-κ B和NF-κ B抑制剂吡咯烷二硫代氨基甲酸铵，并减少组胺诱导的TNF-α和IL-6释放。总之，本研究确定了组胺受体在小胶质细胞上的表达。我们还证实组胺通过H1 R和H4 R-MAPK和PI 3 K/AKT-NF-κ B信号通路诱导活化的小胶质细胞释放TNF-α和IL-6，这将加深对小胶质细胞介导的慢性神经退行性疾病神经炎症症状的理解。
Histamine is a potent mediator of inflammation and a regulator of innate and adaptive immune responses. However, the influence of histamine on microglia, the resident immune cells in the brain, remains uninvestigated. In the present study, we found that microglia can constitutively express all four histamine receptors (H1R, H2R, H3R, and H4R), and the expression of H1R and H4R can be selectively upregulated in primary cultured microglia in a dose-dependent manner by histamine. Histamine can also dose-dependently stimulate microglia activation and subsequently production of proinflammatory factors tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6). The antagonists of H1R and H4R but not H2R and H3R reduced histamine-induced TNF-alpha and IL-6 production, MAPK and PI3K/AKT pathway activation, and mitochondrial membrane potential loss in microglia, suggesting that the actions of histamine are via H1R and H4R. On the other hand, inhibitors of JNK, p38, or PI3K suppressed histamine-induced TNF-alpha and IL-6 release from microglia. Histamine also activated NF-kappa B and ammonium pyrrolidinedithiocarbamate, an inhibitor of NF-kappa B, and reduced histamine-induced TNF-alpha and IL-6 release. In summary, the present study identifies the expression of histamine receptors on microglia. We also demonstrate that histamine induced TNF-alpha and IL-6 release from activated microglia via H1R and H4R-MAPK and PI3K/AKT-NF-kappa B signaling pathway, which will deepen the understanding of microglia-mediated neuroinflammatory symptoms of chronic neurodegenerative disease.