%0 Journal Article
%T Functional Crosstalk between Type I and II Interferon through the Regulated Expression of STAT1
%A Daniel J. Gough
%A Nicole L. Messina
%A Linda Hii
%A Jodee A. Gould
%A Kanaga Sabapathy
%A Ashley P. S. Robertson
%A Joseph A. Trapani
%A David E. Levy
%A Paul J. Hertzog
%A Christopher J. P. Clarke
%A Ricky W. Johnstone
%J PLOS Biology
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pbio.1000361
%X Autocrine priming of cells by small quantities of constitutively produced type I interferon (IFN) is a well-known phenomenon. In the absence of type I IFN priming, cells display attenuated responses to other cytokines, such as anti-viral protection in response to IFN¦Ă. This phenomenon was proposed to be because IFN¦Á/¦Â receptor1 (IFNAR1) is a component of the IFN¦Ă receptor (IFNGR), but our new data are more consistent with a previously proposed model indicating that regulated expression of STAT1 may also play a critical role in the priming process. Initially, we noticed that DNA binding activity of STAT1 was attenuated in c-JunŁż/Łż fibroblasts because they expressed lower levels of STAT1 than wild-type cells. However, expression of STAT1 was rescued by culturing c-JunŁż/Łż fibroblasts in media conditioned by wild-type fibroblasts suggesting they secreted a STAT1-inducing factor. The STAT1-inducing factor in fibroblast-conditioned media was IFN¦Â, as it was inhibited by antibodies to IFNAR1, or when IFN¦Â expression was knocked down in wild-type cells. IFNAR1Łż/Łż fibroblasts, which cannot respond to this priming, also expressed reduced levels of STAT1, which correlated with their poor responses to IFN¦Ă. The lack of priming in IFNAR1Łż/Łż fibroblasts was compensated by over-expression of STAT1, which rescued molecular responses to IFN¦Ă and restored the ability of IFN¦Ă to induce protective anti-viral immunity. This study provides a comprehensive description of the molecular events involved in priming by type I IFN. Adding to the previous working model that proposed an interaction between type I and II IFN receptors, our work and that of others demonstrates that type I IFN primes IFN¦Ă-mediated immune responses by regulating expression of STAT1. This may also explain how type I IFN can additionally prime cells to respond to a range of other cytokines that use STAT1 (e.g., IL-6, M-CSF, IL-10) and suggests a potential mechanism for the changing levels of STAT1 expression observed during viral infection.
%U http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000361