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Amelioration of hepatic fibrosis by NK cell activation
  1. Nidal Muhanna1,
  2. Lina Abu Tair1,
  3. Sarit Doron1,
  4. Johnny Amer1,
  5. Maysa Azzeh2,
  6. Mahmud Mahamid1,
  7. Scott Friedman3,
  8. Rifaat Safadi1
  1. 1Liver and Gastroenterology Units, Division of Medicine, Hadasaah University Medical Center, Jerusalem, Israel
  2. 2Department of Microbiology and Immunology-Medical Research Center, Medical School, Al-Quds University, East Jerusalem-Abu Dies, Palestine
  3. 3Division of Liver Diseases, Mount Sinai School of Medicine, New York, USA
  1. Correspondence to Rifaat Safadi, Liver and Gastroenterology Units, Division of Medicine, Hadassah University Hospital, PO Box 12000, 91120Jerusalem, Israel; safadi{at}hadassah.org.il

Abstract

Background and aims Interactions between hepatic stellate cells (HSCs) and immune cell subsets have emerged as important determinants of liver fibrosis progression and regression. Natural killer (NK) cells have an antifibrotic activity through killing of activated HSCs. In liver injury NK cell expression of activating/inhibitory killer immunoglobulin-related receptors (aKIR/iKIR) and their ratio are significantly increased, while class I major histocompatibilty (MHC) expression by activated HSCs is decreased. The aim of this study was to amplify the antifibrotic activity of NK cells and ameliorate hepatic fibrosis by iKIR silencing.

Methods Human lymphocytes from patients with hepatitis C virus (HCV) infection were transfected with specific iKIR small interfering RNAs (siRNAs) or non-silencing control siRNAs, then co-cultured with a human HSC line and assessed for fibrogenic activity. To induce hepatic fibrosis, carbon tetrachloride was administrated to BALBc SCID-Beige male mice (lacking B/T/NK cells) for 4 weeks. Splenocytes from naive SCID donors (lacking B/T cells but with preserved NK cells) were transfected in vitro with either iKIR siRNA or non-silencing control siRNA, and then were transferred to the fibrotic SCID-Beige recipients.

Results Transfection with iKIR or positive control siRNAs (mice and human) decreased mRNA expression of iKIR and mitogen-acivated protein kinase 1 (MAPK1). Consequently, total NK cells and NK cell degranulation were increased (p=0.01), consistent with NK cell stimulation. Compared with healthy lymphocytes, when HCV lymphocytes were transfected with non-silencing control siRNA and co-cultured with HSCs there was increased α-smooth muscle actin (αSMA) expression, reflecting HSC activation. Expression of αSMA in co-cultures was attenuated when HCV lymphocytes were transfected with iKIR siRNA. In SCID-Beige recipients, hepatic fibrosis and serum alanine aminotransferase (ALT) levels were significantly attenuated as a result of receiving iKIR siRNA.

Conclusions iKIR knockdown stimulates NK cells and promotes their antifibrogenic activity in mice and human co-cultures. These findings have implications for possible immune therapeutic strategies in patients with advanced liver disease.

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Footnotes

  • SF and RS contributed equally to this work.

  • Funding This work was supported by grants from the ‘Binational Scientific Foundation’ and the ‘Israel Scientific Foundation’.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Hadassah University Hospital, Jerusalem, Israel.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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