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.
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.
Ito
Mie
M
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.
Nakagawa
Hiroshi
H
Okada
Toshiya
T
Miyazaki
Syuichi
S
Matsuo
Saburo
S
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
D053148:Caspase 3; D053453:Caspase 9; D005459:Fluorides