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 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-gamma as well as IL-6- and GM-CSF-induced phosphorylation of STAT proteins. Furthermore, IFN-gamma-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.
Dalpke
A H
AH
Institute of Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany.
Opper
S
S
Zimmermann
S
S
Heeg
K
K
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D018899:CpG Islands / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009570:Nitriles / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors
D000276:Adjuvants, Immunologic; D002070:Butadienes; C408982:CPG-oligonucleotide; D002352:Carrier Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009570:Nitriles; D009838:Oligodeoxyribonucleotides; D011506:Proteins; D011725:Pyridines; D012333:RNA, Messenger; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; C113580:U 0126; C093642:SB 203580