Reciprocal regulation of TLR2-mediated IFN-? production by SHP2 and Gsk3?.

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)-? production are poorly understood. Here, we identified Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) as a negative regulator of TLR2-induced IFN-? production. Pharmacological inhibition or reduced expression of SHP2 potentiated TLR2 agonist-mediated IFN-? transcription and STAT1 activation, whereas overexpression of SHP2 impaired IFN-? transcription and STAT1 activation. SHP2 physically associated with the glycogen synthase kinase 3? (Gsk3?) in an agonist-dependent manner. Gsk3? positively regulates transcription of IFN-? following TLR2 stimulation by inhibiting the phosphorylation of SHP2. SHP2 inhibited the transcriptional activity of IRF-1 and IRF-8 at the IFN-? promoter. Remarkably, IRF-1 and IRF-8 are recruited to the IFN-? promoter in a SHP2 phosphatase activity-dependent manner. These findings provide insight into the mechanisms by which SHP2 and Gsk3? work together to modulate TLR2-mediated IFN-? production in macrophages.

SUBMITTER: Park JH 

PROVIDER: S-EPMC5533723 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature