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Microcystin-leucine-arginine (MCLR) is an environmental toxin from harmful algae, which has been linked to hepatotoxicity with high risks associated with liver disease. In this study, we explored the role of MCLR in NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, which are important in regulating inflammatory and immune responses, in human hepatoma cell line HepG2 and primary mouse hepatocytes (PMHs). By in vitro cell-free and luciferase reporter systems, Western blotting with antiphospho-inhibitory protein of NF-κB (IκBα)/c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinase 1/2 (ERK1/2) antibody, it was found that at noncytotoxic concentrations (≤ 20 nM MCLR in PMHs, 1-1000 nM in HepG2), MCLR treatment alone promoted activation of NF-κB and MAPK pathways and modulated TNF-α-induced activation of the 2 pathways in both cell models. By ELISA assay, MCLR was found to induce production of proinflammatory cytokine IL-6 in PMHs. At cytotoxic concentrations (≥ 50 nM MCLR in PMHs), MCLR dramatically reduced cell viability and damaged cell morphology in PMHs, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transmission electron microscopy analysis. These results suggest that MCLR below 20 nM has significant immunomodulatory activities through activation of NF-κB and MAPK signaling pathways, and PMHs are more sensitive to MCLR-induced cytotoxicity than HepG2. To our knowledge, this is the first report showing the immunomodulatory role of MCLR in hepatocytes. Our results provide a better understanding of the molecular mechanisms underlying MCLR-induced hepatotoxicity.

Microcystin-LR Exhibits Immunomodulatory Role in Mouse Primary Hepatocytes Through Activation of the NF-κB and MAPK Signaling Pathways