Abstract
BackgroundMercury 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.MethodsHuman leukemic cultured LAD2 mast cells and normal human umbilical cord blood-derived cultured mast cells (hCBMCs) were stimulated by HgCl2 (0.1-10 μM) for either 10 min for beta-hexosaminidase release or 24 hr for measuring vascular endothelial growth factor (VEGF) and IL-6 release by ELISA.ResultsHgCl2 induced a 2-fold increase in β-hexosaminidase release, and also significant VEGF release at 0.1 and 1 μM (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 μM) to the proinflammatory neuropeptide substance P (SP, 0.1 μM) had synergestic action in inducing VEGF from LAD2 mast cells. HgCl2 also stimulated significant VEGF release (360 ± 100 pg/106 cells at 1 μM, 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 μM) compared to untreated cells (13 ± 25 pg/106 cells, n = 5, p < 0.05). Addition of HgCl2 (0.1 μM) to SP (5 μM) further increased IL-6 release.ConclusionsHgCl2 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.
Highlights
Mercury is known to be neurotoxic, but its effects on the immune system are less well known
Effects of mercury chloride (HgCl2) on mast cell viability LAD2 mast cells and human umbilical cord blood-derived cultured mast cells (hCBMCs) were incubated with HgCl2 for 1 hour or for 24 hours in their respective media, and cell viability was assessed by Trypan blue exclusion
We investigated the effect of HgCl2 on the release of b-hexosaminidase, another secretory granule marker that is released in parallel with histamine
Summary
Mercury is known to be neurotoxic, but its effects on the immune system are less well known. We investigated the effect of mercuric chloride (HgCl2) on human mast cell activation. Heavy metals such as mercury result in neurological injury that may lead to developmental defects, peripheral neuropathies, and enhanced neurodegenerative changes [1]. Sensory, neurological, motor, and behavioral dysfunction similar to those associated with Autism Spectrum Disorders (ASD) [2]. Mercuric chloride (HgCl2) in nontoxic doses induces the release of histamine and cytokines, such as IL-4 and tumor necrosis factor-alpha (TNF-a), from a murine mast cell line and from mouse bone marrowderived cultured mast cells [11]. HgCl2 (100 μM) enhances immunoglobulin E-mediated mediator release from human basophils [12], and histamine release from a rat basophil cell line (RBL-2H3) [13]
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