Reciprocal regulation of TLR2-mediated IFN-ß production by SHP2 and Gsk3ß.

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)-ß production are poorly understood. Here, we identified Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) as a negative regulator of TLR2-induced IFN-ß production. Pharmacological inhibition or reduced expression of SHP2 potentiated TLR2 agonist-mediated IFN-ß transcription and STAT1 activation, whereas overexpression of SHP2 impaired IFN-ß transcription and STAT1 activation. SHP2 physically associated with the glycogen synthase kinase 3ß (Gsk3ß) in an agonist-dependent manner. Gsk3ß positively regulates transcription of IFN-ß following TLR2 stimulation by inhibiting the phosphorylation of SHP2. SHP2 inhibited the transcriptional activity of IRF-1 and IRF-8 at the IFN-ß promoter. Remarkably, IRF-1 and IRF-8 are recruited to the IFN-ß promoter in a SHP2 phosphatase activity-dependent manner. These findings provide insight into the mechanisms by which SHP2 and Gsk3ß work together to modulate TLR2-mediated IFN-ß production in macrophages.