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- Title
USP18-Based Negative Feedback Control Is Induced by Type I and Type III Interferons and Specifically Inactivates Interferon &agr; Response.
- Authors
François-Newton, Véronique; de Freitas Almeida, Gabriel Magno; Payelle-Brogard, Béatrice; Monneron, Danièle; Pichard-Garcia, Lydiane; Piehler, Jacob; Pellegrini, Sandra; Uzé, Gilles
- Abstract
Type I interferons (IFN) are cytokines that are rapidly secreted upon microbial infections and regulate all aspects of the immune response. In humans 15 type I IFN subtypes exist, of which IFN &agr;2 and IFN &bgr; are used in the clinic for treatment of different pathologies. IFN &agr;2 and IFN &bgr; are non redundant in their expression and in their potency to exert specific bioactivities. The more recently identified type III IFNs (3 IFN &lgr; or IL-28/IL-29) bind an unrelated cell-type restricted receptor. Downstream of these two receptor complexes is a shared Jak/Stat pathway. Several mechanisms that contribute to the shut down of the IFN-induced signaling have been described at the molecular level. In particular, it has long been known that type I IFN induces the establishment of a desensitized state. In this work we asked how the IFN-induced desensitization integrates into the network built by the multiple type I IFN subtypes and type III IFNs. We show that priming of cells with either type I IFN or type III IFN interferes with the cell's ability to further respond to all IFN &agr; subtypes. Importantly, primed cells are differentially desensitized in that they retain sensitivity to IFN &bgr;. We show that USP18 is necessary and sufficient to induce differential desensitization, by impairing the formation of functional binding sites for IFN &agr;2. Our data highlight a new type of differential between IFNs &agr and IFN &bgr; and underline a cross-talk between type I and type III IFN. This cross-talk could shed light on the reported genetic variation in the IFN l loci, which has been associated with persistence of hepatitis C virus and patient's response to IFN &agr;2 therapy.
- Subjects
PSYCHOLOGICAL feedback; INTERFERONS; CYTOKINES; IMMUNE response; CELLULAR signal transduction; BIOLOGICAL variation; HEPATITIS C virus
- Publication
PLoS ONE, 2011, Vol 6, Issue 7, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0022200