Abstract
Recent studies showed that melatonin, a well-known pineal hormone that modulates the circadian rhythm, exerts beneficial effects against liver fibrosis. However, mechanisms for its protective action against the fibrotic processes remain incompletely understood. Here, we aimed to explore the effects of the hormone on transforming growth factor-β1 (TGF-β1)-stimulated epithelial–mesenchymal transition (EMT) in AML12 hepatocytes. Pretreatment with melatonin dose-dependently reversed downregulation of an epithelial marker and upregulation of mesenchymal markers after TGF-β1 stimulation. Additionally, melatonin dose-dependently suppressed an increased phosphorylation of Smad2/3 after TGF-β1 treatment. Besides the canonical Smad signaling pathway, an increase in phosphorylation of extracellular signal-regulated kinase 1/2 and p38 was also dose-dependently attenuated by melatonin. The suppressive effect of the hormone on EMT stimulated by TGF-β1 was not affected by luzindole, an antagonist of melatonin membrane receptors, suggesting that its membrane receptors are not required for the inhibitory action of melatonin. Moreover, melatonin suppressed elevation of intracellular reactive oxygen species (ROS) levels in TGF-β1-treated cells. Finally, TGF-β1-stimulated EMT was also inhibited by the antioxidant N-acetylcysteine. Collectively, these results suggest that melatonin prevents TGF-β1-stimulated EMT through suppression of Smad and mitogen-activated protein kinase signaling cascades by deactivating ROS-dependent mechanisms in a membrane receptor-independent manner.
Highlights
Liver fibrosis is attributed to aberrant deposition of extracellular matrix (ECM) in liver parenchyma that leads to hepatic dysfunction
To investigate whether its membrane receptors are required for the inhibitory action of melatonin on epithelial–mesenchymal transition (EMT) stimulated by transforming growth factor-β1 (TGF-β1), we examined the effects of luzindole, a known antagonist of melatonin membrane receptors, at a routinely used concentration (100 μM) [22,23], on the action of melatonin (1mM)
We observed that treatment with an antagonist of melatonin membrane receptors failed to block the effects of melatonin, indicating that melatonin receptors are dispensable for the inhibitory action of melatonin on EMT stimulated by TGF-β1
Summary
Liver fibrosis is attributed to aberrant deposition of extracellular matrix (ECM) in liver parenchyma that leads to hepatic dysfunction. Accumulating evidence suggests that multiple cellular and molecular pathways are implicated in the pathophysiology of liver fibrosis [1]. Epithelial–mesenchymal transition (EMT) of hepatocytes to myofibroblasts is suggested as a crucial process in liver fibrosis [2,3,4,5], there remains some controversy [6,7]. Blocking EMT of hepatocytes might serve as a potential therapeutic or preventive approach against liver fibrosis. The pineal hormone melatonin is well known to modulate the circadian rhythm. The hormone has been shown to display beneficial effects including anti-oxidant and anti-inflammatory
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