Interferon mode of action unveiled

Immunomodulatory treatments such as type I interferons are used to reduce the burden of hepatitis C and multiple sclerosis. However, this therapy is associated with certain side effects such as severe neurotoxicity and neuropsychiatric complications in a significant 30-45 % of patients. To comprehend these unwanted complications one needs to go deeper into the mechanism of action of type I interferons.

In this context, scientists on the EU-funded MBFUSEDIT (Molecular basis for unwanted side-effects during interferon therapy) project investigated the cellular and behavioural consequences of IFN-beta treatment. For this purpose, they generated transgenic mice lacking the IFNAR receptor of IFNalpha/beta in the central nervous system. They worked on demonstrating that IFN-beta binds to IFNARs in brain, glial or other cells causing cognitive impairment and depressive-like behaviour.

to clarify which cells are responsible for the observed toxicity effects, the consortium deleted IFNAR1 in different cell types. Their results indicate that these symptoms stem from receptor activation on brain endothelia. Analysis of the gene expression profile following IFN-beta activation should unveil the precise molecular mechanism.

work towards the identification of key IFN-stimulated genes (ISGs) in the brain revealed an activation of ISG-15 in brain endothelial cells. Further work entails the study of behavioural changes in animals treated with IFN-beta to assess hippocampal synaptic plasticity.

collectively, the findings of the study should provide important insight into the mechanism of action of type I interferons. This information will impact chronic, systemic IFN-beta administration and help reduce unwanted side effects.