Suppressors of Cytokine Signaling (SOCS)-1 and SOCS-3 Are Induced by CpG-DNA and Modulate Cytokine Response in APCs

摘要

During infection, the functional status of the innate immune system is tightly regulated. Although signals resulting in activa have been well characterized, counterregulative mechanisms are poorly understood. Suppressor of cytokine signaling (SO proteins have been characterized as cytokine-inducible negative regulators of Janus kinase/STAT signaling in cells of hemopoi origin. To analyze whether SOCS proteins could also be induced by pathogen-derived stimuli, we investigated the inductioj SOCS-1 and SOCS-3 after triggering of macrophage cell lines, bone marrow-derived dendritic cells, and peritoneal macrophit with CpG-DNA. In this study, we show that CpG-DNA, but not GpC-DNA, induces expression of mRNA for SOCS-1 and SOC in vitro and in vivo. SOCS mRNA expression could be blocked by chloroquine and was independent of protein synthesis. Inhibil of the mitogen-activated protein kinase pathway triggered by CpG-DNA were able to impede induction of SOCS mRNA. C~ DNA triggered synthesis of SOCS proteins that could be detected by Western blotting. SOCS proteins were functional becai they inhibited IFN-y as well as IL-6- and GM-CSF-induced phosphorylation of STAT proteins. Furthermore, IFN-y-indw up-regulation of MHC class II molecules was also prevented. The same effects could be achieved by overexpression of SOC~ Hence, the results indicate a substantial cross-talk between signal pathways within cells. They provide evidence for regulat mechanisms of Janus kinase/STAT signaling after triggering Toll-like receptor signal pathways.