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
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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“Natural killer (NK) cells have an intriguing capacity to clear activated HSCs (91-94).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [91]
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1 retracted
Safadi, R., Zigmond, E., Pappo, O., Shalev, Z., & llan, Y. (2007) · International Immunology · doi:10.1093/intimm/dxm069 · Cited by 35
Self-citationRetractedBataller, R., & Brenner, D. A. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24282 · Cited by 4,958
Activating Receptors and Coreceptors Involved in Human Natural Killer Cell-Mediated Cytolysis
Moretta, A., Bottino, C., Vitale, M., Pende, D., Cantoni, C., Mingari, M. C., Biassoni, R., & Moretta, L. (2001) · Annual Review of Immunology · doi:10.1146/annurev.immunol.19.1.197 · Cited by 1,773
CD107a as a functional marker for the identification of natural killer cell activity
Alter, G., Malenfant, J., & Altfeld, M. A. (2004) · Journal of Immunological Methods · doi:10.1016/j.jim.2004.08.008 · Cited by 1,416
Analysis of Successful Immune Responses in Persons Infected with Hepatitis C Virus
Lechner, F., Wong, D., Dunbar, P. R., Chapman, R. W., Chung, R. T., Dohrenwend, P. B., Robbins, G. K., Phillips, R., Klenerman, P., & Walker, B. D. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.191.9.1499 · Cited by 1,269
Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis
Xu, L., Hui, A. Y., Albanis, E., Arthur, M. J., O’Byrne, S. M., Blaner, W. S., Mukherjee, P., Friedman, S. L., & Eng, F. J. (2004) · Gut · doi:10.1136/gut.2004.042127 · Cited by 1,020
Self-citationREGULATION OF IMMUNE RESPONSES THROUGH INHIBITORY RECEPTORS
Long, E. O. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.875 · Cited by 936
Radaeva, S., Sun, R., Jaruga, B., Nguyen, V. T., Tian, Z., & Gao, B. (2006) · Gastroenterology · doi:10.1053/j.gastro.2005.10.055 · Cited by 610
Apoptotic Body Engulfment by a Human Stellate Cell Line Is Profibrogenic
Canbay, A., Taimr, P., Torok, N., Higuchi, H., Friedman, S., & Gores, G. J. (2003) · Laboratory Investigation · doi:10.1097/01.lab.0000069036.63405.5c · Cited by 417 · cited 1×
“Reduction of activation was achieved when LX2 cells were cultured to confluence in 6-well flasks (Nunc Brand Products, Roskilde, Denmark) with 1% fetal calf serum (FCS).(11) Healthy and HCVderived peripheral blood lymphocytes (PBLs) were co-cultured for 48 h with LX2 cells.”
MethodSelf-citationFriedman, S. L., & Arthur, M. J. P. (1989) · Journal of Clinical Investigation · doi:10.1172/jci114362 · Cited by 404
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- 10.1172/JCI200524282 · DOI · Paper page
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Lee, U. E., & Friedman, S. L. (2011) · Best Practice & Research Clinical Gastroenterology · doi:10.1016/j.bpg.2011.02.005 · Cited by 923
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Hammerich, L., & Tacke, F. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00807-x · Cited by 803
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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
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2010-07-26
- Volume
- 60
- Issue
- 1
- Pages
- 90-98
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- 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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