title: Nitric oxide signals are interlinked with calcium signals in normal pancreatic stellate cells upon oxidative stress and inflammation.
abstract: The mammalian diffuse stellate cell system comprises retinoid-storing cells capable of remarkable transformations from a quiescent to an activated myofibroblast-like phenotype. Activated pancreatic stellate cells (PSCs) attract attention owing to the pivotal role they play in development of tissue fibrosis in chronic pancreatitis and pancreatic cancer. However, little is known about the actual role of PSCs in the normal pancreas. These enigmatic cells have recently been shown to respond to physiological stimuli in a manner that is markedly different from their neighbouring pancreatic acinar cells (PACs). Here, we demonstrate the capacity of PSCs to generate nitric oxide (NO), a free radical messenger mediating, for example, inflammation and vasodilatation. We show that production of cytosolic NO in PSCs is unambiguously related to cytosolic Ca(2+) signals. Only stimuli that evoke Ca(2+) signals in the PSCs elicit consequent NO generation. We provide fresh evidence for the striking difference between signalling pathways in PSCs and adjacent PACs, because PSCs, in contrast to PACs, generate substantial Ca(2+)-mediated and NOS-dependent NO signals. We also show that inhibition of NO generation protects both PSCs and PACs from necrosis. Our results highlight the interplay between Ca(2+) and NO signalling pathways in cell-cell communication, and also identify a potential therapeutic target for anti-inflammatory therapies.
authors.affiliation: Medical Research Council Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK jakubowskam1@cf.ac.uk.
authors.forename: Monika A
authors.identifier: 0000-0002-4899-2606
authors.initials: MA
authors.lastname: Jakubowska
authors.affiliation: Medical Research Council Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK.
authors.forename: Pawel E
authors.identifier: 0000-0001-5582-6588
authors.initials: PE
authors.lastname: Ferdek
authors.affiliation: Medical Research Council Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK.
authors.forename: Oleg V
authors.identifier: 0000-0003-2573-8258
authors.initials: OV
authors.lastname: Gerasimenko
authors.affiliation: Medical Research Council Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK.
authors.forename: Julia V
authors.identifier: 0000-0002-2262-2543
authors.initials: JV
authors.lastname: Gerasimenko
authors.affiliation: Medical Research Council Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK Systems Immunity Research Institute, Cardiff University, Cardiff CF14 4XN, Wales, UK petersenoh@cf.ac.uk.
authors.forename: Ole H
authors.identifier: 0000-0002-6998-0380
authors.initials: OH
authors.lastname: Petersen
mesh_terms: D061354:Acinar Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002450:Cell Communication; D002460:Cell Line; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress; D058954:Pancreatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D002118:Calcium
keywords: calcium; inflammation; nitric oxide; pancreas; stellate cell