Methylmercury-induced IL-6 release requires phospholipase C activities

Abstract

Methylmercury (MeHg) is a neurotoxin capable of causing severe damage to the CNS, especially in the developing fetus. Glia in the CNS release a number of cytokines that are important for proper CNS development and function. We reported earlier that MeHg could induce interleukin-6 (IL-6) release in primary mouse glia. This finding is significant considering previous reports indicating that sustained IL-6 exposure could be detrimental to cerebellar granule neurons, one of the major cellular targets of MeHg cytotoxicity. By using pharmacological antagonists against phophatidycholine- and phosphoinositol-specific phospholipase C, the current study indicated that phospholipase C activity was necessary for MeHg-induced IL-6 release. Results from pharmacological antagonists further suggested that the calcium signaling initiated by phospholipase C appeared essential for this event. In contrast, protein kinase C activity did not appear to be important. Even though mitogen-activated protein kinases were important for IL-6 release in some experimental systems, these enzymes did not appear to be required for MeHg-induced IL-6 release in glia. Based on these data and those reported by us and others, there is a possibility that MeHg-induced phospholipase C activation initiates a calcium signaling that causes phospholipase A2 activation. This, in turn, leads to arachidonic acid and lysophosphatidyl choline generation, both of which are potent inducers for IL-6 release.

Protective effect of a novel peptide against methylmercury-induced toxicity in rat primary astrocytes

“…MeHg has also been reported to stimulate interleukin-6 (IL-6) release from the rat C6 glioma cells, the human U251HF glioma cells and the human retina pigment epithelial (ARPE-19) cells (Chang, 2007). In accordance with our results, exposure of glial cells to MeHg can induce the release of IL-6, a pro-inflammatory cytokine (Chang, 2011), corroborating that the neurotoxicity of MeHg has an inflammatory component. Similarly, inflammatory mediator release is also reported in mast cells following mercury (Hg) exposure (Kempuraj et al, 2010).…”

“…Notably, several earlier studies have indicated a potential role for mediators of inflammation in MeHg toxicity (Chang, 2011, Gardner et al, 2010, Ilback et al, 1996), which could synergistically increase the deleterious pro-oxidant effects of MeHg. Consequently, the present study was carried out examine the effects of IIIM1 on astrocytic cytotoxicity, oxidative injury and inflammation induced by MeHg.…”

Suppression of methylmercury-induced IL-6 and MCP-1 expressions by N-acetylcysteine in U-87MG human astrocytoma cells

“…Since MeHg exposure could induce cytokine releases through not only ROS induction but also other pathways such as cyclic AMP increase [34], stimulation of cytosolic phospholipase A 2 and C ( [8,9], and NF-κB activation [26], further analyses are warranted. NAC significantly suppressed expressions of MCP-1 and IL-6 in a dose-dependent manner in NAC pre-, co-, and post-treatments.…”

Astrocytes Protect Neurons against Methylmercury via ATP/P2Y1 Receptor-Mediated Pathways in Astrocytes

“…Inflammatory responses in glial cells are also involved in several types of neuronal damage. It has been reported that MeHg produces proinflammatory cytokines including interleukin-6 (IL-6) in glial cells [15], [16], [17]. In general, these cytokines facilitate inflammatory responses, leading to deterioration of the neuronal viability.…”