IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation

Sung Joo Park, Takayuki Nakagawa, Hidemitsu Kitamura, Toru Atsumi, Hokuto Kamon, Shin Ichiro Sawa, Daisuke Kamimura, Naoko Ueda, Yoichiro Iwakura, Katsuhiko Ishihara, Masaaki Murakami, Toshio Hirano

Research output: Contribution to journalArticlepeer-review

342 Citations (Scopus)

Abstract

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/GabMAPK (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.

Original languageEnglish
Pages (from-to)3844-3854
Number of pages11
JournalJournal of Immunology
Volume173
Issue number6
DOIs
Publication statusPublished - Sep 15 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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