Immunomodulatory Potency of Microcystin, an Important Water-Polluting Cyanobacterial Toxin

Abstract

Microcystins (MCs) are primarily hepatotoxins produced by cyanobacteria and are responsible for intoxication in humans and animals. There are many incidents of chronic exposure to MCs, which have been attributed to the inappropriate treatment of water supplies or contaminated food. Using RAW 264.7 macrophages, we showed the potency of microcystin-LR (MC-LR) to stimulate production of pro-inflammatory cytokines (tumor necrosis factor α and interleukin-6) as a consequence of fast nuclear factor κB and nitrogen-activated protein kinase activation. In contrast to other studies, the observed effects were not attributed to the intracellular inhibition of protein phosphatases 1/2A due to lack of specific transmembrane transporters for MCs. However, the MC-LR-induced activation of macrophages was effectively inhibited by a specific peptide that blocks signaling of receptors, which play a pivotal role in the innate immune responses. Taken together, we showed for the first time that MC-LR could interfere with macrophage receptors that are responsible for triggering the above-mentioned signaling pathways. These findings provide an interesting mechanistic explanation of some adverse health outcomes associated with toxic cyanobacteria and MCs.

Microcystin-LR Does Not Alter Cell Survival and Intracellular Signaling in Human Bronchial Epithelial Cells

“…Increased phosphorylation was observed in the human HL7702 liver cell line after 48-h exposure to 10 µM MC-LR [72], but not in human HL1-hT1 adult liver stem cells exposed to 1 µM [56], despite toxin uptake was documented in both studies. Elevated P-ERK1/2 levels were additionally reported by Adamovsky et al [31] in murine RAW 264.7 macrophages after 30-min exposure to 1 µM MC-LR, but probably triggered via interactions of the toxin with membrane receptors, independently of MC-LR cellular uptake and inhibition of PPs.…”

Microcystin-leucine-arginine Modulates the Expression Patterns of Proinflammatory Cytokines and an Apoptotic Gene in Chicken Liver

“…MC-LR at the lowest dose (1 ng/mL) increased the mRNA expression of IL-6, whereas the highest dose markedly diminished the expression of this cytokine. In contrast, the production of IL-6 in macrophages (RAW 264.7 cell line) was only slightly induced at the highest concentration (1000 nM) of MC-LR (Adamovsky et al, 2015). The evidence of disturbance of IL-6 potentially indicates the negative effect of MC-LR on the inflammatory reaction after a 6-h treatment.…”

Pharmacological inhibition of TLR4/NF‐κB with TLR4‐IN‐C34 attenuated microcystin‐leucine arginine toxicity in bovine Sertoli cells

“…Previous studies on MC‐LR (Adamovsky et al, ; Adegoke, Wang, Machebe, Adeniran, et al, ; Adegoke, Wang, Machebe, Wang, et al, ) indicated that MC‐LR elicit its toxic effects via TLR4 signaling pathways. Therefore, the TLR4 signaling pathway was made the target for amelioration and attenuation of MC‐LR toxicity in this study.…”

“…According to Huggins et al (), the TLRs, including TLR4, have been shown to play a crucial role in inflammatory diseases. MC‐LR has been reported to induce inflammation in bovine Sertoli cells (Adegoke, Wang, Machebe, Wang, et al, ), in human umbilical vein endothelial cells (Shi, Zhou, & Zhang, ) and activates TLRs, particularly TLR4 in the RAW 264.7 cell line (Adamovsky et al, ). Meanwhile, all TLR signaling pathways culminate in activation of the transcription factor nuclear factor‐kappaB (NF‐κB), which controls the expression of an array of inflammatory cytokine genes (Taro & Shizuo, ).…”