Impaired liver regeneration and increased oval cell numbers following T cell-mediated hepatitis.
The regeneration of liver tissue following transplantation is often complicated by inflammation and tissue damage induced by a number of factors, including ischemia and reperfusion injury and immune reactions to the donor tissue. The purpose of the current study is to characterize the effects of T cell-mediated hepatitis induced by concanavalin A (ConA) on the regenerative response in vivo. Liver regeneration following a partial (70%) hepatectomy (pHx) was associated with elevations in serum enzymes and the induction of key cell cycle proteins (cyclin D, cyclin E, and Stat3) and hepatocyte proliferation. The induction of T cell-mediated hepatitis 4 days before pHx increased serum enzymes 48 hours after pHx, reduced early cyclin D expression and Stat3 activation, and suppressed hepatocyte proliferation. This inhibition of proliferation was also associated with increased expression of p21, the activation of Smad2, the induction of transforming growth factor beta and interferon gamma expression, and reduced hepatic interleukin 6 production. Moreover, the ConA pretreatment increased the numbers of separate oval cell-like CD117(+) cells and hematopoietic-like Sca-1(+) cell populations 48 hours following pHx. The depletion of natural killer (NK) cells, an important component of the innate immune response, did not affect liver injury or ConA-induced impairment of hepatocyte proliferation but did increase the numbers of both CD117-positive and Sca-1-positive cell populations. Finally, splenocytes isolated from ConA-pretreated mice exerted cytotoxicity toward autologous bone marrow cells in an NK cell-dependent manner.


CONCLUSIONS
T cell-mediated hepatitis alters early cytokine responses, reduces hepatocellular regeneration, and induces NK cell-sensitive oval cell and hematopoietic-like cell expansion following pHx.
Hines
Ian N
IN
Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. ihines@med.unc.edu
Kremer
Michael
M
Isayama
Fuyumi
F
Perry
Ashley W
AW
Milton
Richard J
RJ
Black
April L
AL
Byrd
Christy L
CL
Wheeler
Michael D
MD
D000818:Animals; D002470:Cell Survival; D003208:Concanavalin A / Q000633:toxicity; D017930:Genes, Reporter; D006505:Hepatitis / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D007371:Interferon-gamma / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007371:Interferon-gamma