IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation.
Dendritic cells (DCs) orchestrate immune responses according to their state of maturation. In response to infection, DCs differentiate into mature cells that initiate immune responses, while in the absence of infection, most of them remain in an immature form that induces tolerance to self Ags. Understanding what controls these opposing effects is an important goal for vaccine development and prevention of unwanted immune responses. A crucial question is what cytokine(s) regulates DC maturation in the absence of infection. In this study, we show that IL-6 plays a major role in maintaining immature DCs. IL-6 knockout (KO) mice had increased numbers of mature DCs, indicating that IL-6 blocks DC maturation in vivo. We examined this effect further in knockin mice expressing mutant versions of the IL-6 signal transducer gp130, with defective signaling through either Src homology region 2 domain-containing phosphatase 2/Gab/MAPK (gp130(F759/F759)) or STAT3 (gp130(FxxQ/FxxQ)), and combined gp130 and IL-6 defects (gp130(F759/F759)/IL-6 KO mice). Importantly, we found STAT3 activation by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 phosphorylation in DCs was regulated by IL-6 in vivo, and STAT3 was necessary for the IL-6 suppression of bone marrow-derived DC activation/maturation. DC-mediated T cell activation was enhanced in IL-6 KO mice and suppressed in gp130(F759/F759) mice. IL-6 is thus a potent regulator of DC differentiation in vivo, and IL-6-gp130-STAT3 signaling in DCs may represent a critical target for controlling T cell-mediated immune responses in vivo.
Park
Sung-Joo
SJ
Department of Molecular Oncology, Graduate School of Medicine, Osaka University, Suita, Japan.
Nakagawa
Takayuki
T
Kitamura
Hidemitsu
H
Atsumi
Toru
T
Kamon
Hokuto
H
Sawa
Shin-Ichiro
S
Kamimura
Daisuke
D
Ueda
Naoko
N
Iwakura
Yoichiro
Y
Ishihara
Katsuhiko
K
Murakami
Masaaki
M
Hirano
Toshio
T
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130