A complement-IL-4 regulatory circuit controls liver regeneration

J Immunol. 2012 Jan 15;188(2):641-8. doi: 10.4049/jimmunol.1101925. Epub 2011 Dec 19.


The involvement of IL-4 in liver regeneration has not yet been recognized. In this article, we show that IL-4, produced by NKT cells that accumulate in regenerating livers after partial hepatectomy, contributes to this process by regulating the activation of complement after liver resection in mice. The mechanism of this regulation was associated with the maintenance of an appropriate level of IgM in mouse blood, because IgM deposited in liver parenchyma most likely initiated complement activation during liver regeneration. By controlling complement activation, IL-4 regulated the induction of IL-6, thereby influencing a key pathway involved in regenerating liver cell proliferation and survival. Furthermore, the secretion of IL-4 was controlled by complement through the recruitment of NKT cells to regenerating livers. Our study thus reveals the existence of a regulatory feedback mechanism involving complement and IL-4 that controls liver regeneration.

Publication types

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

MeSH terms

  • Animals
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Cell Proliferation
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Complement Activation / genetics
  • Complement Activation / immunology
  • Complement C3 / deficiency
  • Complement C3 / physiology*
  • Cytokines / biosynthesis
  • Hepatectomy
  • Hepatocytes / cytology
  • Hepatocytes / immunology
  • Hepatocytes / metabolism
  • Immunoglobulin M / blood
  • Interleukin-4 / biosynthesis
  • Interleukin-4 / deficiency
  • Interleukin-4 / physiology*
  • Liver Regeneration / genetics
  • Liver Regeneration / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Natural Killer T-Cells / immunology
  • Natural Killer T-Cells / metabolism


  • Complement C3
  • Cytokines
  • Immunoglobulin M
  • Interleukin-4