Nitric oxide inhibits IFN-alpha production of human plasmacytoid dendritic cells partly via a guanosine 3',5'-cyclic monophosphate-dependent pathway.
NO, a free radical gas, is known to be critically involved not only in vascular relaxation but also in host defense. Besides direct bactericidal effects, NO has been shown to inhibit Th1 responses and modulate immune responses in vivo, although the precise mechanism is unclear. In this study, we examined the effect of NO on human plasmacytoid dendritic cells (pDCs) to explore the possibility that NO might affect innate as well as adaptive immunity through pDCs. We found that NO suppressed IFN-alpha production of pDCs partly via a cGMP-dependent mechanism, which was accompanied by down-regulation of IFN regulatory factor 7 expression. Furthermore, treatment of pDCs with NO decreased production of IL-6 and TNF-alpha and up-regulated OX40 ligand expression. In accordance with these changes, pDCs treated with NO plus CpG-oligodeoxynucleotide AAC-30 promoted differentiation of naive CD4(+) T cells into a Th2 phenotype. Moreover, pDCs did not express inducible NO synthase even after treatment with AAC-30, LPS, and several cytokines. These results suggest that exogenous NO and its second messenger, cGMP, alter innate as well as adaptive immune response through modulating the functions of pDCs and may be involved in the pathogenesis of certain Th2-dominant allergic diseases.
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 50 Shogoin Kawara-cho, Sayko-ku, Kyoto 606-8507, Japan.
Rimpei
R
Morita
Takashi
T
Uchiyama
Toshiyuki
T
Hori
D000954:Antigens, Surface / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D006152:Cyclic GMP / Q000502:physiology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D015290:Second Messenger Systems / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology
D000954:Antigens, Surface; C408982:CPG-oligonucleotide; D016207:Cytokines; D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D018836:Inflammation Mediators; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D006152:Cyclic GMP