Bacterial Signals Influence STAT1 Activation by IFN-gamma through Serine Phosphorylation and the Synthesis of SOCS3 Protein

摘要

Bacteria or microbial products like LPS cooperate with IFN-gamma in the process of macrophage activation. However, we found that the influence of LPS on IFN-gamma-mediated macrophage activation changes with the duration of exposure. Short term exposure to LPS and IFN-gamma (<2 h) caused the activation of a STAT1 S727 kinase and phosphorylation of S727 strongly augmented the transcription factor activity of STAT1. In contrast, long term exposure (>4 h) caused downregulation of IFN-gamma-mediated STAT1 tyrosine phosphorylation and transcription. LPS did not affect the expression of IFN-gamma receptor. By contrast, LPS decreased the ability of IFN-gamma to activate JAK1. These effects correlated with the induction of SOCS3 mRNA and protein in LPS-treated macrophages. Our studies stress the relevance of timing macrophage-activating signals during bacterial infection. In addition, they demonstrated the SOCS3 gene as an LPS target gene and its product to mediate negative crosstalk to macrophage-activating cytokines.