title: Inhibition of concanavalin A-induced hepatic injury of mice by bacterial lipopolysaccharide via the induction of IL-6 and the subsequent reduction of IL-4: the cytokine milieu of concanavalin A hepatitis.
abstract: OBJECTIVE
  Liver natural killer 1.1 antigen (NK1)+ T cells and IL-4 play a crucial role in concanavalin-A (Con-A)-induced hepatic injury in mice, and a T helper (Th) 2 immune response was thus suggested to be involved. This study was designed to examine the effect of bacterial lipopolysaccharide (LPS), a strong inducer of a Th 1 immune response, on Con-A hepatic injury and also to clarify further the cytokine milieu of Con-A hepatitis.
  
  
  METHODS
  LPS were injected into mice before Con-A injection to evaluate the effect on hepatic injury. The effect of the pretreatment with various T1 and Th2 cytokines or anti-cytokine antibodies on Con-A hepatitis was also examined.
  
  
  RESULTS
  LPS in quantities > or = 500 ng/mouse, when injected 24 h before Con-A injection, abrogated the Con-A-induced elevation of transaminases, hepatocyte destruction and serum IL-4 elevation. This LPS inhibitory effect was blocked when the mice were injected with either anti-IL-6 antibody before LPS injection or IL-4 before Con-A injection. IL-6, but neither IL-10 nor IL-12 pretreatment suppressed Con-A-induced IL-4 production and hepatitis. NK1+ T cells produced IL-4 while both NK1+ T cells and NK1- T cells produced IFN-gamma. Not only anti-IL-4 antibody but also the anti-IFN-gamma antibody pretreatment inhibited Con-A hepatitis. However, although the anti-IL4 antibody suppressed IL-4 alone, the anti-IFN-gamma Ab unexpectedly inhibited both IFN-gamma and IL-4 elevation, while IL-4 injection evoked a moderate Con-A hepatitis even in the anti-IFN-gamma antibody-treated mice. Furthermore, the IL-4 mutant mice did not develop Con-A hepatitis.
  
  
  CONCLUSIONS
  LPS inhibited Con-A hepatitis by inducing IL-6 and thereby inhibited IL-4 synthesis from NK1+ T cells. Although both IL-4 and IFN-gamma were required for the full induction of Con-A hepatic injury, exogenous IL-4 evoked a moderate Con-A hepatitis, even in the absence of IFN-gamma.
authors.affiliation: Division of Basic Traumatology, National Defense Medical College Research Institute, Namiki, Tokorozawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nishikage
authors.forename: S
authors.initials: S
authors.lastname: Seki
authors.forename: S
authors.initials: S
authors.lastname: Toyabe
authors.forename: T
authors.initials: T
authors.lastname: Abo
authors.forename: Y
authors.initials: Y
authors.lastname: Kagata
authors.forename: T
authors.initials: T
authors.lastname: Iwai
authors.forename: H
authors.initials: H
authors.lastname: Hiraide
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D003208:Concanavalin A / Q000037:antagonists & inhibitors / Q000633:toxicity*; D016753:Interleukin-10 / Q000276:immunology / Q000494:pharmacology; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000235:genetics; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D015375:Receptors, Interleukin-2; D003208:Concanavalin A; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4