title: CpG-A-induced monocyte IFN-gamma-inducible protein-10 production is regulated by plasmacytoid dendritic cell-derived IFN-alpha.
abstract: Unmethylated CpG motifs in bacterial DNA or synthetic oligodeoxynucleotides (ODN) are known for inducing a Th1 cytokine/chemokine environment, but the mechanisms regulating this have been unclear. Recent studies have defined two classes of CpG ODN, CpG-A ODN that induce plasmacytoid dendritic cells (pDC) to secrete very high levels of IFN-alpha, and CpG-B ODN that induce only low levels of IFN-alpha production, but strongly activate B cells. We now demonstrate that a CpG-A ODN directly activates pDC secretion of IFN-alpha and other soluble factors that secondarily induce purified monocytes to secrete high levels of the Th1-promoting chemokine IFN-gamma-inducible protein-10 (IP-10). Cell contact between the monocytes and pDC is not required for this interaction. IFN-alpha is necessary, but only partially sufficient, for this indirect CpG-induced monocyte IP-10 production. Although CpG ODN induce human PBMC to make only very slight amounts of IFN-gamma, we find that these low concentrations synergize with IFN-alpha for inducing monocyte production of IP-10. These studies provide a better understanding of the mechanisms through which CpG ODN create a Th1-like environment.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Sue E
authors.initials: SE
authors.lastname: Blackwell
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Krieg
mesh_terms: D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D018899:CpG Islands / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D016130:Immunophenotyping; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000037:antagonists & inhibitors / Q000145:classification / Q000494:pharmacology*; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D007106:Immune Sera; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; D007371:Interferon-gamma