Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC

Alaa Melhem, Nidal Muhanna, Amal Bishara, Carlos E. Alvarez, Yaron Ilan, Taiser Bishara, Amjad Horani, Mithal Nassar, Scott L. Friedman, Rifaat Safadi

Research output: Contribution to journalArticlepeer-review

228 Scopus citations


Background/Aims: We have investigated the role of natural killer (NK) cells in hepatic fibrogenesis. Mouse NK cells express both inhibitory/activating-killing-immunoglobulin-related-receptors (iKIR/aKIR) specific for Class-I-molecules. Methods: Hepatic fibrosis induced by carbon-tetrachloride (CCl4) was compared between wild-type (WT) male-BALBc; combined-immunodeficiency (SCID, lacking B/T-cells); and SCID-BEIGE-mice (lacking B/T/NK cells), and naive mice. Results: Hepatic fibrosis significantly increased in all CCl4-treated groups. SCID-BEIGE mice had more fibrosis than SCID-mice (P < 0.0001) as assessed by morphometry of sirius-red stained tissue sections. Following fibrosis, hepatic NK cells significantly decreased, the aKIR:iKIR-ratio significantly increased while Class-I expression on HSC decreased (P < 0.001). Both freshly isolated and in situ HSC displayed a significant increase in cellular apoptosis following fibrosis induction. Confocal microscopy demonstrated the direct adhesion of NK cells to HSC in mouse liver sections and in vitro human NK/HSC co-culture. In human HSC there was decreased Class-I expression and increased apoptosis as well, which was further increased following blocking of either HSC-related Class-I or NK-related killer inhibitory receptors. Apoptosis was inhibited by pre-incubation of NK cells with the granzyme inhibitor 3,4-dichloroisocoumarin. Conclusions: During liver injury, NK cells have an anti-fibrotic activity at least in part through stimulation of HSC killing.

Original languageEnglish
Pages (from-to)60-71
Number of pages12
JournalJournal of Hepatology
Issue number1
StatePublished - Jul 2006


  • Hepatic fibrosis
  • Hepatic stellate cells
  • KIR
  • Lymphocytes
  • NK cells
  • SCID


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