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PMID: 15911877 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-gamma.

The Journal of cell biology ·Vol. 169 ·No. 4 ·2005-05-23 ·Pages 603-12

Lin W, Harding HP, Ron D, Popko B

Abstract

Interferon-gamma (IFN-gamma) is believed to contribute to immune-mediated demyelinating disorders by targeting the myelin-producing oligodendrocyte, a cell known to be highly sensitive to the disruption of protein synthesis and to the perturbation of the secretory pathway. We found that apoptosis induced by IFN-gamma in cultured rat oligodendrocytes was associated with endoplasmic reticulum (ER) stress. ER stress also accompanied oligodendrocyte apoptosis and hypomyelination in transgenic mice that inappropriately expressed IFN-gamma in the central nervous system (CNS). Compared with a wild-type genetic background, the enforced expression of IFN-gamma in mice that were heterozygous for a loss of function mutation in pancreatic ER kinase (PERK) dramatically reduced animal survival, promoted CNS hypomyelination, and enhanced oligodendrocyte loss. PERK encodes an ER stress-inducible kinase that phosphorylates eukaryotic translation initiation factor 2alpha and specifically maintains client protein homeostasis in the stressed ER. Therefore, the hypersensitivity of PERK+/- mice to IFN-gamma implicates ER stress in demyelinating disorders that are induced by CNS inflammation.

MeSH Terms
Animals Animals, Newborn Apoptosis/genetics,immunology Demyelinating Diseases/genetics,immunology,metabolism Encephalitis/genetics,immunology,metabolism Endoplasmic Reticulum/immunology,metabolism Eukaryotic Initiation Factor-2/genetics,immunology,metabolism Female Homeostasis Interferon-gamma/genetics,immunology,metabolism Male Mice Mice, Knockout Mice, Transgenic Microscopy, Electron, Transmission Mutation/genetics Myelin Sheath/metabolism,pathology,ultrastructure Oligodendroglia/immunology,metabolism Phosphorylation Rats Stress, Physiological/genetics,immunology,metabolism eIF-2 Kinase/genetics,metabolism
Chemicals
Eukaryotic Initiation Factor-2 Interferon-gamma PERK kinase eIF-2 Kinase
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Lin Wensheng
Jack Miller Center for Peripheral Neuropathy, Department of Neurology, University of Chicago, Chicago, IL 60637, USA.
Harding Heather P
Ron David
Popko Brian
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200502086
Published
2005-05-23
Pages
603-12
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2171696
Subset
IM
Grants
NIDDK NIH HHS · R01 DK047119 · United States
NIEHS NIH HHS · R01 ES008681 · United States
NIEHS NIH HHS · ESO8681 · United States
NIDDK NIH HHS · R37 DK047119 · United States
NINDS NIH HHS · R01 NS034939 · United States
NIDDK NIH HHS · DK47119 · United States
NINDS NIH HHS · NS34939 · United States
External Links
PubMed source DOI: 10.1083/jcb.200502086 PMC Full Text View journal details
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