Reciprocal regulation of TLR2-mediated IFN-β production by SHP2 and Gsk3β

Abstract Toll-like receptor 2 (TLR2) mediates the innate immune response to bacterial lipopeptides and peptidoglycans by stimulating the production of inflammatory cytokines. However, the mechanisms by which TLR2 signaling regulates type I interferon (IFN)-β production are poorly understood. Here, w...

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Autores principales:	Jin Hee Park, Ryeojin Ko, Soo Young Lee
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bc6829427a2f4100a7a6707e016f9cdf
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spelling	oai:doaj.org-article:bc6829427a2f4100a7a6707e016f9cdf2021-12-02T16:06:43ZReciprocal regulation of TLR2-mediated IFN-β production by SHP2 and Gsk3β10.1038/s41598-017-07316-32045-2322https://doaj.org/article/bc6829427a2f4100a7a6707e016f9cdf2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07316-3https://doaj.org/toc/2045-2322Abstract Toll-like receptor 2 (TLR2) mediates the innate immune response to bacterial lipopeptides and peptidoglycans by stimulating the production of inflammatory cytokines. However, the mechanisms by which TLR2 signaling regulates type I interferon (IFN)-β production are poorly understood. Here, we identified Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) as a negative regulator of TLR2-induced IFN-β production. Pharmacological inhibition or reduced expression of SHP2 potentiated TLR2 agonist-mediated IFN-β transcription and STAT1 activation, whereas overexpression of SHP2 impaired IFN-β transcription and STAT1 activation. SHP2 physically associated with the glycogen synthase kinase 3β (Gsk3β) in an agonist-dependent manner. Gsk3β positively regulates transcription of IFN-β following TLR2 stimulation by inhibiting the phosphorylation of SHP2. SHP2 inhibited the transcriptional activity of IRF-1 and IRF-8 at the IFN-β promoter. Remarkably, IRF-1 and IRF-8 are recruited to the IFN-β promoter in a SHP2 phosphatase activity-dependent manner. These findings provide insight into the mechanisms by which SHP2 and Gsk3β work together to modulate TLR2-mediated IFN-β production in macrophages.Jin Hee ParkRyeojin KoSoo Young LeeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jin Hee Park Ryeojin Ko Soo Young Lee Reciprocal regulation of TLR2-mediated IFN-β production by SHP2 and Gsk3β
description	Abstract Toll-like receptor 2 (TLR2) mediates the innate immune response to bacterial lipopeptides and peptidoglycans by stimulating the production of inflammatory cytokines. However, the mechanisms by which TLR2 signaling regulates type I interferon (IFN)-β production are poorly understood. Here, we identified Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) as a negative regulator of TLR2-induced IFN-β production. Pharmacological inhibition or reduced expression of SHP2 potentiated TLR2 agonist-mediated IFN-β transcription and STAT1 activation, whereas overexpression of SHP2 impaired IFN-β transcription and STAT1 activation. SHP2 physically associated with the glycogen synthase kinase 3β (Gsk3β) in an agonist-dependent manner. Gsk3β positively regulates transcription of IFN-β following TLR2 stimulation by inhibiting the phosphorylation of SHP2. SHP2 inhibited the transcriptional activity of IRF-1 and IRF-8 at the IFN-β promoter. Remarkably, IRF-1 and IRF-8 are recruited to the IFN-β promoter in a SHP2 phosphatase activity-dependent manner. These findings provide insight into the mechanisms by which SHP2 and Gsk3β work together to modulate TLR2-mediated IFN-β production in macrophages.
format	article
author	Jin Hee Park Ryeojin Ko Soo Young Lee
author_facet	Jin Hee Park Ryeojin Ko Soo Young Lee
author_sort	Jin Hee Park
title	Reciprocal regulation of TLR2-mediated IFN-β production by SHP2 and Gsk3β
title_short	Reciprocal regulation of TLR2-mediated IFN-β production by SHP2 and Gsk3β
title_full	Reciprocal regulation of TLR2-mediated IFN-β production by SHP2 and Gsk3β
title_fullStr	Reciprocal regulation of TLR2-mediated IFN-β production by SHP2 and Gsk3β
title_full_unstemmed	Reciprocal regulation of TLR2-mediated IFN-β production by SHP2 and Gsk3β
title_sort	reciprocal regulation of tlr2-mediated ifn-β production by shp2 and gsk3β
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/bc6829427a2f4100a7a6707e016f9cdf
work_keys_str_mv	AT jinheepark reciprocalregulationoftlr2mediatedifnbproductionbyshp2andgsk3b AT ryeojinko reciprocalregulationoftlr2mediatedifnbproductionbyshp2andgsk3b AT sooyounglee reciprocalregulationoftlr2mediatedifnbproductionbyshp2andgsk3b
_version_	1718384927238520832

Reciprocal regulation of TLR2-mediated IFN-β production by SHP2 and Gsk3β

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