Study of melatonin-mediated effects on various hepatic inflammatory responses stimulated by IL-6 in a new HepG2-on-a-chip platform.

Hepatocytes exhibit diverse reactions upon stimulation with the interleukin IL-6, mainly in the context of inflammation and energy metabolism. Melatonin has been shown to exert pleiotropic protective actions, such as anti-inflammation and anti-oxidative stress on many cell- and organ-types. The key role of the liver to maintain homeostasis and metabolic regulation prompted us to evaluate the direct modification of IL-6-induced alterations in HepG2 cells in a chip by melatonin. IL-6 administration was followed by the reduced expression and activity of MRP2, a loss of CYP1A activity, and the decline of PXR expression. Other effects were the induction of acute phase responses (reduced albumin production as well as increased CRP and hepcidin expression) and lowered expression of CREB3L3. IL-6 affected also the mitochondrial membrane potential together with elevated mitochondrial superoxide generation, and glycogen deposition was reduced. Melatonin counteracted all observed IL-6-induced alterations except the rise in CRP release and CYP1A activity. Altogether, this new in vitro model can be applied to investigate hepatic inflammatory responses stimulated by IL-6, and these results indicate that hepatocellular inflammatory responses to IL-6 are mitigated by melatonin.