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: | , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2017
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/bc6829427a2f4100a7a6707e016f9cdf |
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| Sumario: | 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. |
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