Selective regulation of interleukin-10 production via Janus kinase pathway in murine conventional dendritic cells.
In this study, we examined the role of JAKs in regulation of inflammatory versus anti-inflammatory cytokine balance in murine conventional dendritic cells (DCs). Highly purified lipopolysaccharide (upLPS) combined with imiquimod (IQ) synergistically induced IL-10 production by DCs, while each ligand alone showed a slight effect on the IL-10 production. Marked phosphorylation of JAK2, STAT1 and STAT3 was detected in DCs following upLPS plus IQ stimulation. Blocking the JAK pathway by JAK inhibitor I (JAKi) resulted in significant inhibition of IL-10 production by the DCs. However, JAKi showed negligible effect on the DC production of IL-12, IL-6 and TNF-alpha. JAKi completely blocked the TLR-mediated STATs activation, and attenuated the activation of Akt, a downstream effector of PI3K, in DCs stimulated by upLPS plus IQ. LY294002, a specific inhibitor of PI3K, markedly inhibited the DC production of IL-10. Thus, JAK-PI3K axis appeared to be responsible for the IL-10 production by DCs.
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.
Noriyuki
N
Hirata
Yoshiki
Y
Yanagawa
Kazuya
K
Iwabuchi
Kazunori
K
Onoé
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077271:Imiquimod; D016753:Interleukin-10 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D015415:Biomarkers; D002867:Chromones; D004791:Enzyme Inhibitors; D008024:Ligands; D008070:Lipopolysaccharides; D009025:Morpholines; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D051193:Toll-Like Receptors; D016753:Interleukin-10; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000077271:Imiquimod