Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs

During infection, the functional status of the innate immune system is tigh tly regulated. Although signals resulting in activation have been well char acterized, counterregulative mechanisms are poorly understood. Suppressor o f cytokine signaling (SOCS) proteins have been characterized as cytokine-in ducible negative regulators of Janus kinase/STAT signaling in cells of hemo poietic origin. To analyze whether SOCS proteins could also be induced by p athogen-derived stimuli, we investigated the induction of SOCS-1 and SOCS-3 after triggering of macrophage cell lines, bone marrow-derived dendritic c ells, and peritoneal macrophages with CpG-DNA. In this study, we show that CpG-DNA, but not GpC-DNA, induces expression of mRNA for SOCS-1 and SOCS-3 in vitro and in vivo. SOCS mRNA expression could be blocked by chloroquine and was independent of protein synthesis. Inhibitors of the mitogen-activat ed protein kinase pathway triggered by CpG-DNA were able to impede inductio n of SOCS mRNA. CpG-DNA triggered synthesis of SOCS proteins that could be detected by Western blotting. SOCS proteins were functional because they in hibited IFN-gamma as well as IL-6- and GM-CSF-induced phosphorylation of ST AT proteins. Furthermore, IFN-gamma -induced up-regulation of MHC class II molecules was also prevented. The same effects could be achieved by overexp ression of SOCS-1. Hence, the results indicate a substantial cross-talk bet ween signal pathways within cells. They provide evidence for regulative mec hanisms of Janus kinase/STAT signaling after triggering Toll-like receptor signal pathways.