MC-LR-induced interaction between M2 macrophage and biliary epithelial cell promotes biliary epithelial cell proliferation and migration through regulating STAT3

Abstract

Microcystin-leucine-arginine (MC-LR) was produced by toxic cyanobacteria, which has been shown to have potent hepatotoxicity. Our previous study has proved that MC-LR were able to promote intrahepatic biliary epithelial cell excessive proliferation. However, the underlying mechanism is not yet entirely clarified. Herein, mice were fed with different concentrations (1, 7.5, 15, or 30 mu g/L) of MC-LR by drinking water for 6 months. As the concentration of MC-LR increased, a growing number of macrophages were evaluated in the portal area of the mouse liver. Next, we built a co-culture system to explore the interaction between macrophages (THP-1 cells) and human intrahepatic biliary epithelial cells (HiBECs) in the presence of MC-LR. Under the exposure of MC-LR, HiBECs secreted a large amount of inflammatory factors (IL-6, IL-8, IL-1 beta, COX-2, XCL-1) and chemokine (MCP-1), which produced a huge chemotactic effect on THP-1 cells and induced elevation of the surface M2-subtype biomarkers (IL-10, CD163, CCL22, and Arg-1). In turn, high content of IL-6 in the medium activated JAK2/STAT3, MEK/ERK, and PI3K/AKT pathways in HiBECs, inducing HiBEC abnormal proliferation and migration. Together, these results suggested that MC-LR-mediated interaction between HiBECs and macrophages induced the M2-type polarization of macrophages, and activated IL-6/JAK2/STAT3, MEK/ERK, and PI3K/AKT pathways in HiBECs, further enhanced cell proliferation, improved cell migration, and hindered cell apoptosis by activating p-STAT3.