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

Arch Toxicol. 2009 Feb;83(2):151-9. doi: 10.1007/s00204-008-0341-7. Epub 2008 Aug 12.

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.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Death / drug effects
  • Cytoplasmic Granules / metabolism*
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum, Rough / drug effects*
  • Endoplasmic Reticulum, Rough / metabolism
  • Endoplasmic Reticulum, Rough / ultrastructure
  • Fluorides / pharmacology*
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Male
  • Pancreas, Exocrine / drug effects*
  • Pancreas, Exocrine / enzymology
  • Pancreas, Exocrine / ultrastructure
  • Phagosomes / metabolism
  • Phagosomes / ultrastructure
  • Protein Folding
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Time Factors

Substances

  • Caspase 3
  • Caspase 9
  • Fluorides