CpG DNA induced IL-12 p40 gene activation is independent of STAT1 activation or production of interferon consensus sequence binding protein.
The host immune system responds to CpG motifs in bacterial DNA by rapidly producing proinflammatory cytokines. The host response to CpG DNA resembles, in many ways, the response to bacterial lipopolysaccharide (LPS). While both agents can induce a powerful inflammatory response, CpG DNA promotes Th1 and suppresses Th2 immunity. The regulation of macrophage IL-12 p40 secretion in response to stimulation with LPS and interferon-gamma (IFN-gamma) is dependent on the action of a nuclear transacting factor, interferon consensus sequence binding protein (ICSBP), a STAT1-dependent gene product. We found that CpG DNA induced IL-12 p40 secretion by macrophages from mice with either disrupted STAT1 or ICSBP genes. Additionally, CpG DNA did not induce translocation of transcription factors that bind to the gamma-activated sequence in the ICSBP gene nor did CpG DNA induce ICSBP transcription. CpG DNA, which activates macrophages by the TLR9 pathway, is a strong inducer of IL-12 p40, yet does so independently of IFN-gamma, STAT1 or ICSBP. Thus, CpG DNA-induced IL-12 p40 secretion is mediated by one or more signaling elements distinct from those induced by either LPS or IFN-gamma.
Bradford
Mary
M
Department of Veterans Affairs Medical Center, University of Iowa, College of Medicine, Iowa City, Iowa 52246, USA.
Schroeder
Arin  J
A
Morse
Herbert C
HC
Vogel
Stefanie N
SN
Cowdery
John S
JS
D000818:Animals; D002460:Cell Line; D018899:CpG Islands; D004269:DNA, Bacterial / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics*; D053762:Interleukin-12 Subunit p40; D008264:Macrophages; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009841:Oligonucleotides / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D021122:Protein Subunits / Q000235:genetics*; D012097:Repressor Proteins / Q000096:biosynthesis*; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D000099185:Interferon Regulatory Factor-8
D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D018664:Interleukin-12; D053762:Interleukin-12 Subunit p40; D009841:Oligonucleotides; D021122:Protein Subunits; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D015534:Trans-Activators; D000099185:Interferon Regulatory Factor-8; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse