ArticleHepatology (Baltimore, Md.)2013
Invariant NKT cell activation induces neutrophil accumulation and hepatitis: opposite regulation by IL-4 and IFN-γ.
Article in Hepatology (Baltimore, Md.), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
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Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 citations in OpenAlex.
- Alterations in Immune Cell Profiles in the Liver in Diabetes Mellitus: A Systematic Review.International journal of molecular sciences · 2025Pooled it
- The Pro-Inflammatory Action of Different Pathogen-Associated Molecular Patterns in Porcine Hepatic and Intestinal Cell Cultures.Animals : an open access journal from MDPI · 2026Article
- Modulation of Inflammation-Driven Hepatocarcinogenesis: The Hepatic Immune Microenvironment, Gut-Liver Axis, and Neuroregulation.Journal of hepatocellular carcinoma · 2026Review
- Immunological mechanisms and emerging therapeutic targets in alcohol-associated liver disease.Cellular & molecular immunology · 2025Review
- Kupffer Cells Regulate iNKT Cells Through Il-12 to Mitigate the Extent of APAP-Induced Damage in the Liver.Journal of cellular and molecular medicine · 2025Article
- Modulation of STAT6 signaling for hepatoprotection.Frontiers in pharmacology · 2025Review
- Innate immune regulation in inflammation resolution and liver regeneration in drug-induced liver injury.Archives of toxicology · 2025Review
- Soluble CD46 as a diagnostic marker of hepatic steatosis.EBioMedicine · 2024Article
- Role of immune cell interactions in alcohol-associated liver diseases.Liver research (Beijing, China) · 2024Review
- invariant Natural Killer T cell therapy as a novel therapeutic approach in hematological malignancies.Frontiers in transplantation · 2024Review
- Targeting adrenergic receptors to mitigate invariant natural killer T cells-induced acute liver injury.iScience · 2023Article
- Activation of cDCs and iNKT cells contributes to triptolide-induced hepatotoxicity via STING signaling pathway and endoplasmic reticulum stress.Cell biology and toxicology · 2023Article
- Interorgan communication with the liver: novel mechanisms and therapeutic targets.Frontiers in immunology · 2023Review
- Innate immunity and early liver inflammation.Frontiers in immunology · 2023Review
- Myeloid peroxisome proliferator-activated receptor α deficiency accelerates liver regeneration via IL-6/STAT3 pathway after 2/3 partial hepatectomy in mice.Hepatobiliary surgery and nutrition · 2022Article
- The 'Danse Macabre'-Neutrophils the Interactive Partner Affecting Oral Cancer Outcomes.Frontiers in immunology · 2022Review
- New insights into iNKT cells and their roles in liver diseases.Frontiers in immunology · 2022Review
- HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160.The Journal of experimental medicine · 2021Article
- Repeated α-GalCer Administration Induces a Type 2 Cytokine-Biased iNKT Cell Response and Exacerbates Atopic Skin Inflammation in Vα14Biomedicines · 2021Article
- SRSF1 plays a critical role in invariant natural killer T cell development and function.Cellular & molecular immunology · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
unlabelledAlpha-Galactosylceramide (α-Galcer), a specific agonist for invariant natural killer T (iNKT) cells, is being evaluated in clinical trials for the treatment of viral hepatitis and liver cancer. However, the results from α-Galcer treatment are mixed, partially because of the variety of cytokines produced by activated iNKT cells that have an unknown synergistic effect on the progression of liver disease. It is well documented that injection of α-Galcer induces mild hepatitis with a rapid elevation in the levels of interleukin (IL)-4 and a delayed elevation in the levels of interferon-gamma (IFN-γ), and both of these cytokines are thought to mediate many functions of iNKT cells. Surprisingly, genetic deletion of both IL-4 and IFN-γ aggravated, rather than abolished, α-Galcer-induced iNKT hepatitis. Moreover, genetic ablation of IL-4, the IL-4 receptor, or its downstream signaling molecule signal transducer and activator of transcription (STAT)6 ameliorated α-Galcer-induced neutrophil infiltration, liver injury, and hepatitis. In contrast, genetic deletion of IFN-γ, the IFN-γ receptor, or its downstream signaling molecule STAT1 enhanced liver neutrophil accumulation, thereby exacerbating liver injury and hepatitis. Moreover, depletion of neutrophils eradicated α-Galcer-induced liver injury in wild-type, STAT1 knockout, and IFN-γ knockout mice.
conclusionOur results propose a model in which activated iNKT cells rapidly release IL-4, which promotes neutrophil survival and hepatitis but also sequentially produce IFN-γ, which acts in a negative feedback loop to ameliorate iNKT hepatitis by inducing neutrophil apoptosis. Thus, modification of iNKT production of IL-4 and IFN-γ may have the potential to improve the efficacy of α-Galcer in the treatment of liver disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.