Title
Down-modulation of type 1 interferon responses by receptor cross-competition for a shared Jak kinase Down-modulation of type 1 interferon responses by receptor cross-competition for a shared Jak kinase
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
Baltimore, Md ,
Subject
Human medicine
Source (journal)
Journal of biological chemistry. - Baltimore, Md
Volume/pages
276(2001) :50 , p. 47004-47012
ISSN
0021-9258
ISI
000172768500046
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Abstract
In contrast to the large number of class I and II cytokine receptors, only four Janus kinase (Jak) proteins are expressed in mammalian cells, implying the shared use of these kinases by many different receptor complexes. Consequently, if receptor numbers exceed the amount of available Jak, cross-interference patterns can be expected. We have engineered two model cellular systems expressing two different exogenous Tyk2-interacting receptors. A receptor chimera was generated wherein the extracellular part of the interferon type 1 receptor (Ifnar1) component of the interferon-/ receptor is replaced by the equivalent domain of the erythropoietin receptor. Despite Tyk2 activation, erythropoietin treatment of cells expressing this erythropoietin receptor/Ifnar1 chimera did not evoke any detectable IFN-type response. However, a dose-dependent interference with signal transduction via the endogenous Ifnar complex was found for STAT1, STAT2, STAT3, Tyk2, and Jak1 activation, for gene induction, and for antiviral activity. In a similar approach, cells expressing the 1 chain of the interleukin-12 receptor showed a reduced transcriptional response to IFN- as well as reduced STAT and kinase activation. In both model systems, titration of the Tyk2 kinase away from the Ifnar1 receptor chain accounts for the observed cross-interference.
E-info
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