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 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.
Conzelmann
Michael
M
German Cancer Research Center, Department of Molecular Oncology/Hematology, Heidelberg, Germany.
Wagner
Andreas H
AH
Hildebrandt
Anke
A
Rodionova
Elena
E
Hess
Michael
M
Zota
Annika
A
Giese
Thomas
T
Falk
Christine S
CS
Ho
Anthony D
AD
Dreger
Peter
P
Hecker
Markus
M
Luft
Thomas
T
D000938:Antigen-Presenting Cells / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism; D019013:CD40 Antigens / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis*; D053613:Janus Kinase 1 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000099185:Interferon Regulatory Factor-8
D019013:CD40 Antigens; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D016753:Interleukin-10; D018664:Interleukin-12; D053613:Janus Kinase 1; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D000099185:Interferon Regulatory Factor-8; C494079:STAT1 protein, human