The persistence of interleukin-6 is regulated by a blood buffer system derived from dendritic cells

Immunity. 2021 Feb 9;54(2):235-246.e5. doi: 10.1016/j.immuni.2020.12.001. Epub 2020 Dec 22.


The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions.

Keywords: antibody response; immune defense; inflammation; regulation; signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADAM17 Protein
  • Animals
  • Cell Differentiation
  • Dendritic Cells / immunology*
  • Immunity, Humoral
  • Immunoglobulin M / immunology
  • Inflammation
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / immunology
  • Interleukin-6 / blood*
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology*
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Plasma Cells / immunology
  • Receptors, Interleukin-6 / blood
  • Receptors, Interleukin-6 / immunology
  • Signal Transduction / immunology
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 7 / immunology


  • Il6ra protein, mouse
  • Immunoglobulin M
  • Interferon Regulatory Factors
  • Interleukin-6
  • Irf5 protein, mouse
  • Membrane Glycoproteins
  • Receptors, Interleukin-6
  • Tlr4 protein, mouse
  • Tlr7 protein, mouse
  • Toll-Like Receptor 4
  • Toll-Like Receptor 7
  • interleukin-6, mouse
  • ADAM17 Protein
  • Adam17 protein, mouse