title: ER-stress caused by accumulated intracistanal granules activates autophagy through a different signal pathway from unfolded protein response in exocrine pancreas cells of rats exposed to fluoride.
abstract: In rat exocrine pancreas cells, fluoride treatment causes autophagy resulting from intracisternal granule accumulation. Excessive autophagy might promote a type of programmed cell death different from apoptosis. To clarify how fluoride-induced autophagy and subsequent cell death occurs, we investigated morphological and biochemical changes in exocrine pancreas cells of rats subcutaneously injected with NaF saline solution at 20 mg/kg dose twice daily for 4 days. Intracisternal granule, excessive autophagy and ribosomal degranulation were observed in fluoride-exposed cells, occasionally with necrotic changes. Fluoride-induced rER-stress increased eIF-2alpha phosphorylation and CHOP expression, but did not affect GRP78. Spliced XBP-1 expression was decreased in damaged cells. These findings indicate that rER-stress by intracisternal granule accumulation lead to autophagy in exocrine pancreas cells without UPR, suggesting that signal process of autophagy differs from that of UPR-apoptosis. It is likely that intense degranulation is a turning point that damaged cells change over from autophagy, cell-protective process, to cell-death process.
authors.affiliation: Laboratory of Toxicology, Course of Veterinary Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, 1-1 Gakuen-cho, Nakaku, Sakai 599-8531, Japan.
authors.forename: Mie
authors.initials: M
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Toshiya
authors.initials: T
authors.lastname: Okada
authors.forename: Syuichi
authors.initials: S
authors.lastname: Miyazaki
authors.forename: Saburo
authors.initials: S
authors.lastname: Matsuo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018870:Endoplasmic Reticulum, Rough / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D005459:Fluorides / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D046790:Pancreas, Exocrine / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D017510:Protein Folding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D053148:Caspase 3; D053453:Caspase 9; D005459:Fluorides