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Institute of Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany
During infection, the functional status of the innate immune system
is tightly regulated. Although signals resulting in activation have
been well characterized, counterregulative mechanisms are poorly
understood. Suppressor of cytokine signaling (SOCS) proteins have been
characterized as cytokine-inducible negative regulators of Janus
kinase/STAT signaling in cells of hemopoietic origin. To analyze
whether SOCS proteins could also be induced by pathogen-derived
stimuli, we investigated the induction of SOCS-1 and SOCS-3 after
triggering of macrophage cell lines, bone marrow-derived dendritic
cells, 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-activated protein kinase pathway triggered by
CpG-DNA were able to impede induction of SOCS mRNA. CpG-DNA triggered
synthesis of SOCS proteins that could be detected by Western blotting.
SOCS proteins were functional because they inhibited IFN-
as well as
IL-6- and GM-CSF-induced phosphorylation of STAT proteins. Furthermore,
IFN--induced up-regulation of MHC class II molecules was also
prevented. The same effects could be achieved by overexpression of
SOCS-1. Hence, the results indicate a substantial cross-talk between
signal pathways within cells. They provide evidence for regulative
mechanisms of Janus kinase/STAT signaling after triggering Toll-like
receptor signal pathways.
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