A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells.
Dendritic cells (DC) produce interleukin-12 (IL-12) in response to Toll-like receptor (TLR) activation. Two major TLR signaling pathways participate in the response to pathogens: the nuclear factor-kappaB (NF-kappaB)-dependent pathway leading to inflammatory cytokine secretion including IL-12 and the interferon (IFN)-dependent pathway inducing type I IFN and IFN-regulated genes. Here we show that the two pathways cooperate and are likely both necessary for inducing an optimal response to pathogens. R-848/Resiquimod (TLR7 ligand in the mouse and TLR7/8 ligand in human) synergized with poly(I:C) (TLR3 ligand) or lipopolysaccharide (LPS; TLR4 ligand) in inducing high levels of bioactive IL-12p70 secretion and IFN-beta mRNA accumulation by mouse bone marrow-derived DC (BM-DC). Strikingly, IL-12p70 but not IL-12p40 secretion was strongly reduced in BM-DC from STAT1(-/-) and IFNAR(-/-) mice. STAT1 tyrosine-phosphorylation, IL-12p35, and IFN-beta mRNA accumulation were strongly inhibited in IFNAR(-/-) BM-DC activated with the TLR ligand combinations. Similar observation were obtained in human TLR8-expressing monocyte-derived DC (moDC) using neutralizing anti-IFNAR2 antibodies, although results also pointed to a possible involvement of IFN-lambda1 (also known as IL-29). This suggests that TLR engagement on DC induces endogenous IFNs that further synergize with the NF-kappaB pathway for optimal IL-12p70 secretion. Moreover, analysis of interferon regulatory factors (IRF) regulation in moDC suggests a role for IRF7/8 in mediating IRF3-independent type I IFN and possibly IL-12p35 synthesis in response to TLR7/8.
Gautier
Grégory
G
Laboratory for Immunological Research, Schering-Plough, 69571 Dardilly, France.
Humbert
Martine
M
Deauvieau
Florence
F
Scuiller
Mathieu
M
Hiscott
John
J
Bates
Elizabeth E M
EE
Trinchieri
Giorgio
G
Caux
Christophe
C
Garrone
Pierre
P
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology*; D010766:Phosphorylation; D053633:Receptor, Interferon alpha-beta; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017471:Receptors, Interferon / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
D017931:DNA Primers; D004268:DNA-Binding Proteins; C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; C494232:IRF3 protein, human; C508034:Ifnar2 protein, mouse; D007093:Imidazoles; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D053633:Receptor, Interferon alpha-beta; D018664:Interleukin-12; C402365:resiquimod