IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation
Open accessAbstract
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 (gp130F759/F759) or STAT3 (gp130FxxQ/FxxQ), and combined gp130 and IL-6 defects (gp130F759/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 gp130F759/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.
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IL-6-STAT3 signaling inhibits the LPS-induced maturation of dendritic cells and dendritic cell-mediated activation of T cells in vivo.
“Further, IL-6–STAT3 signaling inhibits the LPS-induced maturation of DCs and DC-mediated activation of T cells in vivo (204).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [204]
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- Authors
- Park, S.-J., Nakagawa, T., Kitamura, H., Atsumi, T., Kamon, H., Sawa, S.-I., Kamimura, D., Ueda, N., Iwakura, Y., Ishihara, K., Murakami, M., & Hirano, T.
- Affiliations
- RIKEN (JP)
- The University of Osaka (JP)
- Department of Molecular Oncology, Graduate School of Medicine, Osaka University , Suita, Osaka ,
- Institute of Medical Science, The University of Tokyo (JP)
- Corresponding author
- Kamimura, Daisuke
- Ishihara, Katsuhiko
- Murakami, Masaaki
- Hirano, Toshio
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-09
- Volume
- 173
- Issue
- 6
- Pages
- 3844-3854
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2152765064
- Cited by
- 519
- References
- 3
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 31 · 2023: 40 · 2022: 19 · 2021: 35 · 2020: 30 · 2019: 30 · 2018: 23 · 2017: 22 · 2016: 19 · 2015: 20 · 2014: 18 · 2013: 28 · 2012: 19
- FWCI
- 8.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Kanae Foundation for the Promotion of Medical Science
- Uniformed Services University of the Health Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- interleukin-6, dendritic cell maturation, STAT3 activation, gp130, IL-6 signaling, T cell activation, bone marrow-derived dendritic cells, immune tolerance, mitogen-activated protein kinase, vaccine development
- MeSH terms
- Animals, Bone Marrow Cells, Cell Differentiation, Dendritic Cells, DNA-Binding Proteins, Growth Inhibitors, Humans, Lipopolysaccharides, Membrane Glycoproteins, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Spleen, T-Lymphocytes, Signal Transduction, Trans-Activators, Antigens, CD, Interleukin-6, Antigen Presentation, Mice, Knockout, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice
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