Pancreatic stellate/myofibroblast cells express G-protein-coupled melatonin receptor 1

Abstract

In chronic pancreatitis and pancreatic cancer, progressive fibrosis with the accumulation of extracellular matrix occurs. The main extracellular matrix-producing cell types are retinoid-storing pancreatic stellate cells (PSCs) of mesenchymal origin. Similar to liver stellate cells, quiescent PSCs undergo activation and acquire a myofibroblast-like phenotype in response to pro-fibrogenic mediators (reactive oxygen species, cytokines and toxic metabolites). Activated PSCs differ in their differentiation stage and are characterized by the expression of glial fibrillary-acidic protein, alpha-smooth muscle actin, and nestin. As G-protein-coupled receptors were described to regulate PSC differentiation, we investigated tissue samples from patients with pancreatitis and ductal pancreatic adenocarcinoma for the expression of G-protein-coupled melatonin receptors MT1 and MT2 by double immunofluorescence staining. We show that MT1, but not MT2, is occasionally expressed in PSCs in normal tissue, while in the diseased tissue MT1 is found at high rates in activated PSCs at all stages, and, additionally, in ductal epithelial cells. It is speculated that MT1 activation by its ligand melatonin regulates proliferation and differentiation of PSCs. Prevention of myofibroblast formation by MT1 activation could explain favourable effects of the pineal hormone melatonin on the outcome of pancreatic fibrosis in animal models.