title: A complement-IL-4 regulatory circuit controls liver regeneration.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: DeAngelis
authors.forename: Maciej M
authors.initials: MM
authors.lastname: Markiewski
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kourtzelis
authors.forename: Stavros
authors.initials: S
authors.lastname: Rafail
authors.forename: Maria
authors.initials: M
authors.lastname: Syriga
authors.forename: Adam
authors.initials: A
authors.lastname: Sandor
authors.forename: Mano R
authors.initials: MR
authors.lastname: Maurya
authors.forename: Shakti
authors.initials: S
authors.lastname: Gupta
authors.forename: Shankar
authors.initials: S
authors.lastname: Subramaniam
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D003167:Complement Activation / Q000235:genetics / Q000276:immunology; D003176:Complement C3 / Q000172:deficiency / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007075:Immunoglobulin M / Q000097:blood; D015847:Interleukin-4 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D008115:Liver Regeneration / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D003176:Complement C3; D016207:Cytokines; D007075:Immunoglobulin M; D015847:Interleukin-4