title: CpG DNA induces self and cross-hyporesponsiveness of RAW264.7 cells in response to CpG DNA and lipopolysaccharide: alterations in IL-1 receptor-associated kinase expression.
abstract: Exposure of macrophages to LPS induces a state of hyporesponsiveness to subsequent challenge with LPS. It has not been known whether previous exposure to CpG DNA induces a similar suppressive response to subsequent stimulation with CpG DNA. In the present study, we demonstrate that pretreatment with CpG DNA induces suppression of cytokine release in a murine macrophage-like cell RAW264.7 in response to subsequent challenge by CpG DNA. Additionally, CpG DNA-mediated activation of mitogen-activated protein kinases, including c-Jun NH(2)-terminal kinase, extracellular signal-regulated kinase, and p38, and activation of transcription factors AP-1, CREB, NF-kappaB, and STAT1 are greatly suppressed in the cells pre-exposed to CpG DNA. Pretreatment with CpG DNA also partially inhibited LPS-mediated production of cytokines and activation of mitogen-activated protein kinases and transcription factors. Neither LPS nor CpG DNA treatment inhibited Toll-like receptor 4, MD2, Toll-like receptor 9, myeloid differentiation factor 88, Toll/IL-1R domain-containing adaptor protein, Tollip, and TNF-alpha receptor-associated factor 6 expression. Interestingly, CpG DNA or LPS stimulation led to the inhibition of IL-1R-associated kinase expression. These results indicate that CpG DNA-induced refractory of RAW264.7 cells may be, at least in part, due to suppressed IL-1R-associated kinase expression.
authors.affiliation: Children's Foundation Research Center at Le Bonheur Children's Hospital, and Department of Pediatrics, University of Tennessee Health Science Center, Memphis 38103, USA.
authors.forename: Seon-Ju
authors.initials: SJ
authors.lastname: Yeo
authors.forename: Jae-Geun
authors.initials: JG
authors.lastname: Yoon
authors.forename: Soon-Cheol
authors.initials: SC
authors.lastname: Hong
authors.forename: Ae-Kyung
authors.initials: AK
authors.lastname: Yi
mesh_terms: D000818:Animals; D002460:Cell Line; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology*; D018899:CpG Islands / Q000276:immunology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004247:DNA / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D029721:Drosophila Proteins; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000096:biosynthesis*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D017634:Self Tolerance / Q000187:drug effects / Q000276:immunology*; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D047428:Protein Kinase Inhibitors; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014157:Transcription Factors; D004247:DNA; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D020928:Mitogen-Activated Protein Kinases