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T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6
Open accessAbstract
This study investigates the molecular mechanisms underlying the induction of and protection from T cell activation-associated hepatic injury. When BALB/c mice were given a single intravenous injection of concanavalin A (Con A) (> or = 0.3 mg/mouse), they developed acute hepatic injury as assessed by a striking increase in plasma transaminase levels within 24 h. Histopathologically, only the liver was injured while moderate infiltration of T cells and polymorphonuclear cells occurred in the portal areas and around the central veins. The induction of hepatic injury was dependent on the existence as well as the activation of T cells, as untreated BALB/c nu/nu mice or BALB/c mice pretreated with a T cell-specific immunosuppressive drug, FK506, failed to develop disease. Significant increases in the levels of various cytokines in the plasma were detected before an increase in plasma transaminase levels. Within 1 h after Con A injection, tumor necrosis factor (TNF) levels peaked, this being followed by production of two other inflammatory cytokines, interleukin 6 (IL-6) and IL-1. Passive immunization with anti-TNF but not with anti-IL-1 or anti-IL-6 antibody, conferred significant levels of protection. Moreover, administration of rIL-6 before Con A injection resulted in an IL-6 dose-dependent protection. A single administration of a given dose of rIL-6 completely inhibited the release of transaminases, whereas the same regimen induced only 40-50% inhibition of TNF production. More than 80% inhibition of TNF production required four consecutive rIL-6 injections. These results indicate that: (a) TNFs are critical cytokines for inducing T cell activation-associated (Con A-induced) hepatitis; (b) the induction of hepatitis is almost completely controlled by rIL-6; and (c) rIL-6 exerts its protective effect through multiple mechanisms including the reduction of TNF production.
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In the citing paper
“Earlier studies demonstrated that IL-6 attenuated liver injury in Con A-induced hepatitis (1).”
From The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury (2005) · cites this paper as [1]
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In the citing paper
“Increasing evidence demonstrates that IL-6 has a protective role during liver injury.”
From The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury (2005) · cites this paper as [1]
In the citing paper
“Moreover, it was shown that IL‐6‐deficient knockout mice have elevated levels of TNF‐α (214).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [214]
In the citing paper
“and levels of TNF-α are markedly elevated in anti-IL-6-treated mice and in IL-6-deficient knockout mice [67, 68], indicating that circulating IL-6 is involved in the regulation of TNF-α levels.”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [68]
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“Moreover, it was shown that IL‐6‐deficient knockout mice have elevated levels of TNF‐α (214).”
BackgroundInfluential
Metadata
- Authors
- Mizuhara, H., O'Neill, E., Seki, N., Ogawa, T., Kusunoki, C., Otsuka, K., Satoh, S., Niwa, M., Senoh, H., & Fujiwara, H.
- Affiliations
- New Drug Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 1994-05-01
- Volume
- 179
- Issue
- 5
- Pages
- 1529-1537
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2191474
- OpenAlex
- W2131520834
- Cited by
- 517
- References
- 42
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 9 · 2022: 8 · 2021: 9 · 2020: 13 · 2019: 8 · 2018: 17 · 2017: 18 · 2016: 20 · 2015: 18 · 2014: 15 · 2013: 15 · 2012: 21
- FWCI
- 9.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- concanavalin A-induced hepatitis, TNF-α, interleukin-6, interleukin-1, cytokines, liver injury, transaminases, T cell depletion, FK506, liver inflammation
- MeSH terms
- Animals, Antibodies, Concanavalin A, Female, Hepatitis, Animal, Humans, Immunohistochemistry, Liver, Lymphocyte Activation, Mice, Inbred BALB C, T-Lymphocytes, Tumor Necrosis Factor-alpha, Interleukin-6, Mice
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