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IFN-γ activated JAK1 shifts CD40-induced cytokine profiles in human antigen-presenting cells toward high IL-12p70 and low IL-10 production

CD40Ligand (CD40L) represents a strong endogenous danger signal associated with chronic inflammatory disease. CD40L induces activation of antigen-presenting cells (APCs) such as DCs, monocytes, B-cells and endothelial cells. However, CD40 activation alone, whilst inducing IL-10 production, is insuff...

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Hauptverfasser: Conzelmann, Michael (VerfasserIn) , Wagner, Andreas H. (VerfasserIn) , Hildebrandt, Anke (VerfasserIn) , Rodionova, Elena (VerfasserIn) , Hess, Michael (VerfasserIn) , Zota, Annika (VerfasserIn) , Giese, Thomas (VerfasserIn) , Falk, Christine Susanne (VerfasserIn) , Ho, Anthony Dick (VerfasserIn) , Dreger, Peter (VerfasserIn) , Hecker, Markus (VerfasserIn) , Luft, Thomas (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 13 August 2010
In: Biochemical pharmacology
Year: 2010, Jahrgang: 80, Heft: 12, Pages: 2074-2086
ISSN:1873-2968
DOI:10.1016/j.bcp.2010.07.040
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.bcp.2010.07.040
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Verfasserangaben:Michael Conzelmann, Andreas H. Wagner, Anke Hildebrandt, Elena Rodionova, Michael Hess, Annika Zota, Thomas Giese, Christine S. Falk, Anthony D. Ho, Peter Dreger, Markus Hecker, Thomas Luft
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Zusammenfassung:CD40Ligand (CD40L) represents a strong endogenous danger signal associated with chronic inflammatory disease. CD40L induces activation of antigen-presenting cells (APCs) such as DCs, monocytes, B-cells and endothelial cells. However, CD40 activation alone, whilst inducing IL-10 production, is insufficient to induce interleukin (IL)-12p70 release in human APCs suggesting that additional cytokine signals (e.g. GM-CSF, IL-4 or IFN-γ) are required for the induction of a pro-inflammatory cytokine profile. We demonstrate that IFN-γ-induced Janus kinase 1 (JAK1) enhances CD40-induced IL-12p70 release whilst simultaneously inhibiting IL-10 synthesis, resulting in a pro-inflammatory phenotype of CD40L-activated dendritic cells (DCs). JAK2 mediated enhancing effects on IL-12p70 but did not inhibit IL-10 release, whereas Tyk2 mediated inhibitory effects on IL-12p70 release in this system. The mechanism by which complementary IFN-γ/JAK activities affect IL-12p70 production involves STAT1 activation and de novo induction of interferon-responsive factors (IRF)-1 and IRF-8. Simultaneously, JAK1 was unique in inhibiting IL-10 synthesis via STAT1 and IRF-8 with both transcription factors binding to the IL-10 promoter. We demonstrate that CD40- and JAK/STAT/IRF-signalling pathways are strictly complementary for the induction of a pro-inflammatory cytokine profile in human APCs. This suggests that a number of CD40 effects in chronic inflammatory diseases might be weakened by targeting JAK/STAT.
Beschreibung:Gesehen am 07.06.2023
Beschreibung:Online Resource
ISSN:1873-2968
DOI:10.1016/j.bcp.2010.07.040

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