Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / pharmacology*
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Aminoquinolines / pharmacology*
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Animals
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Biomarkers / metabolism
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Chromones / pharmacology
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Drug Synergism
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Enzyme Inhibitors / pharmacology
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Imiquimod
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Interleukin-10 / agonists
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Interleukin-10 / antagonists & inhibitors
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Interleukin-10 / biosynthesis
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Interleukin-10 / immunology*
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Janus Kinases / antagonists & inhibitors
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Janus Kinases / immunology*
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Janus Kinases / metabolism
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Ligands
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Lipopolysaccharides / pharmacology*
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinase Kinases / drug effects
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Mitogen-Activated Protein Kinase Kinases / immunology
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Morpholines / pharmacology
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NF-kappa B / drug effects
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NF-kappa B / immunology
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NF-kappa B / metabolism
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphatidylinositol 3-Kinases / immunology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Phosphorylation / immunology
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STAT1 Transcription Factor / immunology
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STAT1 Transcription Factor / metabolism
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STAT3 Transcription Factor / immunology
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STAT3 Transcription Factor / metabolism
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Toll-Like Receptors / immunology
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Toll-Like Receptors / metabolism
Substances
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Adjuvants, Immunologic
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Aminoquinolines
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Biomarkers
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Chromones
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Enzyme Inhibitors
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Ligands
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Lipopolysaccharides
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Morpholines
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NF-kappa B
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Stat1 protein, mouse
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Stat3 protein, mouse
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Toll-Like Receptors
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Interleukin-10
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Phosphatidylinositol 3-Kinases
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Janus Kinases
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Mitogen-Activated Protein Kinase Kinases
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Imiquimod