Interleukin-2 and interleukin-12 mediate distinct effector mechanisms of liver allograft rejection

Liver Transpl Surg. 1997 Mar;3(2):118-29. doi: 10.1002/lt.500030204.


Interleukin-2 (IL-2), interleukin-12 (IL-12) or interleukin-4 (IL-4) were administered postoperatively to otherwise spontaneously accepting mouse liver allograft recipients (C57BL/10-->C3H) to test whether TH1 cytokines are critical mediators of rejection in this model. The induction of rejection at days 5 to 7 by exogenously administered IL-2 and IL-12, but not IL-4, suggests that mouse liver allograft rejection can be induced by TH1 cytokines; however, there appeared to be differences in the mechanism by which these cytokines induce liver rejection. IL-2 administration was accompanied by an increased intragraft infiltration of CD4+ and CD8+ cells and an up-regulation of natural killer (NK), lymphokine-activated killer (LAK), allospecific cytotoxic killer (CTL) activity and perforin mRNA when compared with media-treated controls. In contrast, exogenous IL-12 treatment was associated with a suppression of CTL, NK, and LAK activity compared with controls but an enhanced infiltration of F4/80+ macrophages as determined by immunohistochemistry. Determination of cytokine mRNA profiles by semi-quantitative reverse transcription polymerase chain reaction showed the up-regulation of interferon (IFN)-gamma, IL-4, IL-6, and IL-10 mRNA with IL-2 treatment when compared with media-treated controls. Interestingly, IL-2 mRNA was down-regulated in these animals, suggesting a negative feedback mechanism in IL-2 regulation. IL-12 treatment resulted in the up-regulation of IFN-gamma, IL-6, and IL-10 mRNA, but not IL-2 or IL-4 mRNA. Higher complement-directed cytotoxic antibody titers were seen in IL-12-treated recipients compared with controls, whereas IL-2 treatment showed no apparent differences in antibody titers compared with media treatment. These in vivo observations were mimicked in a mixed leukocyte reaction by supplementing the reaction with IL-2, IL-12, or media. These results suggest that rejection of mouse liver allografts may involve more than one distinct cellular immunological effector mechanism. One is mediated by IL-2 and appears to favor alloreactive CTL, whereas the other pathway is mediated by IL-12/IFN-gamma and involves macrophages and cytotoxic antibodies largely resembling a delayed-type hypersensitivity reaction.

MeSH terms

  • Animals
  • Complement Activation / drug effects
  • Cytotoxicity Tests, Immunologic
  • Graft Rejection / chemically induced
  • Graft Rejection / immunology*
  • Graft Rejection / metabolism
  • Graft Rejection / pathology*
  • Immunohistochemistry
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-12 / metabolism
  • Interleukin-12 / pharmacology*
  • Interleukin-2 / metabolism
  • Interleukin-2 / pharmacology*
  • Interleukin-4 / metabolism
  • Interleukin-4 / pharmacology
  • Interleukin-6 / metabolism
  • Liver Transplantation / immunology*
  • Liver Transplantation / pathology
  • Lymphocyte Culture Test, Mixed
  • Macrophages / drug effects
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • RNA, Messenger / analysis
  • T-Lymphocyte Subsets / drug effects
  • Time Factors


  • Interleukin-2
  • Interleukin-6
  • RNA, Messenger
  • Interleukin-10
  • Interleukin-12
  • Interleukin-4
  • Interferon-gamma