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

Abstract

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-γ as well as IL-6- and GM-CSF-induced phosphorylation of STAT proteins. Furthermore, IFN-γ-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.

BAFF synthesis by rheumatoid synoviocytes is positively controlled by α5β1 integrin stimulation and is negatively regulated by tumor necrosis factor α and toll‐like receptor ligands

“…The inhibitory effect of CpG on BAFF synthesis is not dependent on IL-6, since CpG failed to induce IL-6 release by activated FLS, as has also been observed in leukocytes (40), whereas they can directly induce the expression of SOCS-1 and SOCS-3 (41). Overall, our findings showed that BAFF secretion by resident cells of target organs of autoimmunity is tightly regulated by a complex network involving innate immunity and cytokines, with positive and negative controls that are dependent on the receptors and pathways triggered.…”

Increased macrophage activation mediated through toll‐like receptors in rheumatoid arthritis

“…It is possible that activation through an endogenous TLR ligand, such as heat-shock proteins (HSPs) (17,47), may predispose the macrophages to heightened activation by subsequent exposure to microbial TLR ligands (48,49). Alternatively, it is also feasible that prior in vivo exposure to potential endogenous TLR-2 or TLR-4 ligands may have induced tolerance to repeat stimulation (50,51), partially reducing the response expected for the level of TLR-2 or TLR-4 expression in some RA patients, and possibly accounting for the lack of association between TLR expression and response to TLR ligand in RA patients.…”

Early Growth Response-1 Regulates Lipopolysaccharide-induced Suppressor of Cytokine Signaling-1 Transcription

“…Previous evidence has suggested that the regulation is dependent upon autocrine and paracrine cytokine signaling mechanisms, whereby the treatment of macrophages with LPS induces cytokines such as IFN-␣/␤ to upregulate SOCS-1 expression (19,20). The JAK-STATindependent nature of TLR signaling suggested the possibility of an additional pathway for the regulation of SOCS-1 transcription.…”