Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts Medical Center, Boston, MA 02111, USA.
J Neuroinflammation. 2010 Mar 11;7:20. doi: 10.1186/1742-2094-7-20.
Mercury is known to be neurotoxic, but its effects on the immune system are less well known. Mast cells are involved in allergic reactions, but also in innate and acquired immunity, as well as in inflammation. Many patients with Autism Spectrum Disorders (ASD) have "allergic" symptoms; moreover, the prevalence of ASD in patients with mastocytosis, characterized by numerous hyperactive mast cells in most tissues, is 10-fold higher than the general population suggesting mast cell involvement. We, therefore, investigated the effect of mercuric chloride (HgCl2) on human mast cell activation.
Human leukemic cultured LAD2 mast cells and normal human umbilical cord blood-derived cultured mast cells (hCBMCs) were stimulated by HgCl2 (0.1-10 microM) for either 10 min for beta-hexosaminidase release or 24 hr for measuring vascular endothelial growth factor (VEGF) and IL-6 release by ELISA.
HgCl2 induced a 2-fold increase in beta-hexosaminidase release, and also significant VEGF release at 0.1 and 1 microM (311 +/- 32 pg/106 cells and 443 +/- 143 pg/106 cells, respectively) from LAD2 mast cells compared to control cells (227 +/- 17 pg/106 cells, n = 5, p < 0.05). Addition of HgCl2 (0.1 microM) to the proinflammatory neuropeptide substance P (SP, 0.1 microM) had synergestic action in inducing VEGF from LAD2 mast cells. HgCl2 also stimulated significant VEGF release (360 +/- 100 pg/106 cells at 1 microM, n = 5, p < 0.05) from hCBMCs compared to control cells (182 +/- 57 pg/106 cells), and IL-6 release (466 +/- 57 pg/106 cells at 0.1 microM) compared to untreated cells (13 +/- 25 pg/106 cells, n = 5, p < 0.05). Addition of HgCl2 (0.1 microM) to SP (5 microM) further increased IL-6 release.
HgCl2 stimulates VEGF and IL-6 release from human mast cells. This phenomenon could disrupt the blood-brain-barrier and permit brain inflammation. As a result, the findings of the present study provide a biological mechanism for how low levels of mercury may contribute to ASD pathogenesis.
汞是众所周知的神经毒素，但它对免疫系统的影响知之甚少。肥大细胞参与过敏反应，但也参与先天和获得性免疫以及炎症。许多自闭症谱系障碍（ASD）患者有“过敏”症状；此外，肥大细胞增多症患者的 ASD 患病率高出普通人群 10 倍，其特征是大多数组织中存在大量过度活跃的肥大细胞，提示肥大细胞参与其中。因此，我们研究了氯化汞（HgCl2）对人肥大细胞激活的影响。
用 HgCl2（0.1-10 μM）刺激人白血病培养的 LAD2 肥大细胞和正常人脐带血培养的肥大细胞（hCBMCs）10 分钟以释放β-己糖胺酶，或 24 小时以酶联免疫吸附试验（ELISA）测量血管内皮生长因子（VEGF）和白细胞介素 6（IL-6）的释放。
HgCl2 诱导β-己糖胺酶释放增加 2 倍，还诱导 LAD2 肥大细胞中 VEGF 显著释放，浓度分别为 0.1 和 1 μM 时为 311 ± 32 pg/106 细胞和 443 ± 143 pg/106 细胞，与对照细胞（227 ± 17 pg/106 细胞，n = 5，p < 0.05）相比。HgCl2（0.1 μM）与前炎症神经肽 P 物质（SP，0.1 μM）联合作用可协同诱导 LAD2 肥大细胞中 VEGF 的释放。HgCl2 还刺激 hCBMCs 中 VEGF 显著释放（1 μM 时为 360 ± 100 pg/106 细胞，n = 5，p < 0.05），与对照细胞（182 ± 57 pg/106 细胞）相比，IL-6 释放（0.1 μM 时为 466 ± 57 pg/106 细胞）与未处理细胞（13 ± 25 pg/106 细胞，n = 5，p < 0.05）相比。HgCl2（0.1 μM）与 SP（5 μM）联合作用进一步增加了 IL-6 的释放。
HgCl2 刺激人肥大细胞释放 VEGF 和白细胞介素 6。这种现象可能会破坏血脑屏障并允许大脑炎症。因此，本研究的结果为低水平汞如何导致 ASD 发病机制提供了生物学机制。
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