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Cited by 127Liver physiology and pathologyImmune Cell Function and InteractionLiver Diseases and Immunity

The DOI matches its Crossref record; 26 of the 26 references it cites were found in a registry or an index.

Amelioration of hepatic fibrosis by NK cell activation

Muhanna, Nidal, Tair, Lina Abu, Doron, Sarit, Amer, Johnny, Azzeh, Maysa, Mahamid, Mahmud, Friedman, Scott, Safadi, Rifaat·2011·Gut
DOI 10.1136/gut.2010.211136
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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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Metadata

Authors
Muhanna, N., Tair, L. A., Doron, S., Amer, J., Azzeh, M., Mahamid, M., Friedman, S., & Safadi, R.
Affiliations
  • Hadassah Medical Center (IL)
  • Al-Quds University (PS)
Corresponding author
Safadi, Rifaat
ORCID
Venue
Gut
Publisher
BMJ
Published
2010-07-26
Volume
60
Issue
1
Pages
90-98
ISSN
  • 0017-5749 (ISSN-L)
  • 1468-3288
DOI
10.1136/gut.2010.211136
OpenAlex
W2102422505
Cited by
127
References
25
Citations by year
2026: 1 · 2025: 3 · 2024: 8 · 2023: 6 · 2022: 2 · 2021: 11 · 2020: 12 · 2019: 8 · 2018: 8 · 2017: 4 · 2016: 9 · 2015: 11 · 2014: 9 · 2013: 14 · 2012: 10
FWCI
7.31
Type
journal article
Language
en
Open access
closed
Locations
  • Gut (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
liver fibrosis, natural killer cells, hepatic stellate cells, NK cell activation, antifibrotic activity, hepatitis C virus, siRNA knockdown, NK cell degranulation, MAPK1, alpha-smooth muscle actin, liver injury, carbon tetrachloride
MeSH terms
Animals, Cells, Cultured, Humans, Killer Cells, Natural, Liver Cirrhosis, Liver Cirrhosis, Experimental, Lymphocyte Activation, Male, Mice, Inbred BALB C, Middle Aged, RNA, Messenger, Spleen, Genetic Therapy, Mice, SCID, Coculture Techniques, Adoptive Transfer, RNA, Small Interfering, Mice, Receptors, KIR, Gene Knockdown Techniques

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