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A little stress is good: IFN-γ, demyelination, and multiple sclerosis
Jason R. Lees, Anne H. Cross
Jason R. Lees, Anne H. Cross
Published February 1, 2007
Citation Information: J Clin Invest. 2007;117(2):297-299. https://doi.org/10.1172/JCI31254.
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Commentary

A little stress is good: IFN-γ, demyelination, and multiple sclerosis

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Abstract

The exact role(s) of the cytokine IFN-γ in the demyelinating disease multiple sclerosis remain controversial, with evidence suggesting both detrimental and protective effects of the cytokine in MS and MS models such as EAE. The study by Lin and coworkers in this issue of the JCI produces evidence that protective effects of IFN-γ on mature oligodendrocytes during EAE induction are mediated via activation of the pancreatic ER kinase (PERK), resulting in induction of the endoplasmic reticular stress response pathway (see the related article beginning on page 448). Modulation of this stress pathway has what we believe to be novel therapeutic potential for MS.

Authors

Jason R. Lees, Anne H. Cross

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Figure 1

A model of the differential responses to IFN-γ of ODCs during their differentiation.

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A model of the differential responses to IFN-γ of ODCs during their diff...
The schematic shows the response of ODCs, at 2 different stages of development, to IFN-γ delivered to the CNS before EAE onset in mice. Low constitutive protein production allows mature ODCs (top left) to survive the increase in ER stress that is associated with the initial interaction with IFN-γ (bottom left). Having survived the original stressor, mature ODCs induce activation of PERK. PERK activation in turn induces eIF2α phosphorylation, ultimately allowing ODCs to acquire resistance to further ER stress. The acquired resistance to ER stress protects cells from apoptotic mechanisms associated with EAE, allowing the cells to maintain functional myelin sheaths and concomitantly reducing clinical symptoms observed in MS. In contrast, a high level of constitutive protein production in developing ODCs (top right) results in toxic levels of ER stress following IFN-γ treatment (bottom right), resulting in an increased risk of apoptosis in developing ODCs.

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