Functional crosstalk between type I and II interferon through the regulated expression of STAT1.

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 IFNgamma. This phenomenon was propos...

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Autores principales:	Daniel J Gough, Nicole L Messina, Linda Hii, Jodee A Gould, Kanaga Sabapathy, Ashley P S Robertson, Joseph A Trapani, David E Levy, Paul J Hertzog, Christopher J P Clarke, Ricky W Johnstone
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/534b147fa2ff4ed686a5638eb2e548af
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spelling	oai:doaj.org-article:534b147fa2ff4ed686a5638eb2e548af2021-12-02T19:54:52ZFunctional crosstalk between type I and II interferon through the regulated expression of STAT1.1544-91731545-788510.1371/journal.pbio.1000361https://doaj.org/article/534b147fa2ff4ed686a5638eb2e548af2010-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20436908/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Autocrine 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 IFNgamma. This phenomenon was proposed to be because IFNalpha/beta receptor1 (IFNAR1) is a component of the IFNgamma 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-Jun(-/-) fibroblasts because they expressed lower levels of STAT1 than wild-type cells. However, expression of STAT1 was rescued by culturing c-Jun(-/-) fibroblasts in media conditioned by wild-type fibroblasts suggesting they secreted a STAT1-inducing factor. The STAT1-inducing factor in fibroblast-conditioned media was IFNbeta, as it was inhibited by antibodies to IFNAR1, or when IFNbeta expression was knocked down in wild-type cells. IFNAR1(-/-) fibroblasts, which cannot respond to this priming, also expressed reduced levels of STAT1, which correlated with their poor responses to IFNgamma. The lack of priming in IFNAR1(-/-) fibroblasts was compensated by over-expression of STAT1, which rescued molecular responses to IFNgamma and restored the ability of IFNgamma 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 IFNgamma-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.Daniel J GoughNicole L MessinaLinda HiiJodee A GouldKanaga SabapathyAshley P S RobertsonJoseph A TrapaniDavid E LevyPaul J HertzogChristopher J P ClarkeRicky W JohnstonePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 8, Iss 4, p e1000361 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Daniel J Gough Nicole L Messina Linda Hii Jodee A Gould Kanaga Sabapathy Ashley P S Robertson Joseph A Trapani David E Levy Paul J Hertzog Christopher J P Clarke Ricky W Johnstone Functional crosstalk between type I and II interferon through the regulated expression of STAT1.
description	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 IFNgamma. This phenomenon was proposed to be because IFNalpha/beta receptor1 (IFNAR1) is a component of the IFNgamma 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-Jun(-/-) fibroblasts because they expressed lower levels of STAT1 than wild-type cells. However, expression of STAT1 was rescued by culturing c-Jun(-/-) fibroblasts in media conditioned by wild-type fibroblasts suggesting they secreted a STAT1-inducing factor. The STAT1-inducing factor in fibroblast-conditioned media was IFNbeta, as it was inhibited by antibodies to IFNAR1, or when IFNbeta expression was knocked down in wild-type cells. IFNAR1(-/-) fibroblasts, which cannot respond to this priming, also expressed reduced levels of STAT1, which correlated with their poor responses to IFNgamma. The lack of priming in IFNAR1(-/-) fibroblasts was compensated by over-expression of STAT1, which rescued molecular responses to IFNgamma and restored the ability of IFNgamma 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 IFNgamma-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.
format	article
author	Daniel J Gough Nicole L Messina Linda Hii Jodee A Gould Kanaga Sabapathy Ashley P S Robertson Joseph A Trapani David E Levy Paul J Hertzog Christopher J P Clarke Ricky W Johnstone
author_facet	Daniel J Gough Nicole L Messina Linda Hii Jodee A Gould Kanaga Sabapathy Ashley P S Robertson Joseph A Trapani David E Levy Paul J Hertzog Christopher J P Clarke Ricky W Johnstone
author_sort	Daniel J Gough
title	Functional crosstalk between type I and II interferon through the regulated expression of STAT1.
title_short	Functional crosstalk between type I and II interferon through the regulated expression of STAT1.
title_full	Functional crosstalk between type I and II interferon through the regulated expression of STAT1.
title_fullStr	Functional crosstalk between type I and II interferon through the regulated expression of STAT1.
title_full_unstemmed	Functional crosstalk between type I and II interferon through the regulated expression of STAT1.
title_sort	functional crosstalk between type i and ii interferon through the regulated expression of stat1.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/534b147fa2ff4ed686a5638eb2e548af
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Functional crosstalk between type I and II interferon through the regulated expression of STAT1.

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