The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index; 15 of the 24 sources its claims cite were checked for support.
The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury
Open accessAbstract
Increasing evidence demonstrates that IL-6 has a protective role during liver injury. IL-6 activates intracellular pathways via the gp130 receptor. In order to identify IL-6-gp130 pathways involved in mediating liver protection, we analyzed hepatocyte-specific gp130 knockout mice in a concanavalin A-induced (Con A-induced) model of immune-mediated hepatitis. We demonstrated that IL-6-gp130-dependent pathways in hepatocytes alone are sufficient for triggering protection in Con A-induced hepatitis. gp130-STAT3 signaling in hepatocytes mediates the IL-6-triggered protective effect. This was demonstrated by analysis of IL-6-induced protection in mice selectively deficient for gp130-dependent STAT1/3 or gp130-SHP2-RAS signaling in hepatocytes. To identify IL-6-gp130-STAT1/3 dependently expressed liver-protective factors, we performed gene array analysis of hepatic gene expression in hepatocyte-specific gp130(-/-) mice as well as in gp130-STAT1/3- and gp130-SHP2-RAS-MAPK-deficient mice. The mouse IL-8 ortholog KC (also known as Gro-alpha) and serum amyloid A2 (SAA2) was identified as differentially IL-6-gp130-STAT3-regulated genes. Hepatic expression of KC and SAA2 mediate the liver-protective potential of IL-6, since treatment with recombinant KC or serum SAA2 effectively reduced liver injury during Con A-induced hepatitis. In summary, this study defines IL-6-gp130-STAT3-dependent gene expression in hepatocytes that mediates IL-6-triggered protection in immune-mediated Con A-induced hepatitis. Additionally, we identified the IL-6-gp130-STAT3-dependent proteins KC and SAA2 as new candidates for therapeutic targets in liver diseases.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
In a mouse Con A model of T cell–mediated hepatitis, IL-6–gp130–STAT3 signaling specifically in hepatocytes is necessary and sufficient for IL-6-triggered liver protection. The authors identify KC and SAA2 as IL-6–gp130–STAT3–dependent hepatocyte proteins that can themselves reduce Con A–induced liver injury.
Key findings
- Hepatocyte gp130 is required for IL-6 protection: IL-6 pretreatment completely blocked AST increases in wild-type mice, but failed to protect hepatocyte-specific gp130-null mice; all `alfpCre gp130 LoxP/LoxP` mice died within the first 20 hours after Con A, whereas NaCl- and IL-6-treated wild-type animals survived.
- The protective signal is gp130-STAT3, not gp130-SHP2-RAS-MAPK: IL-6 pretreatment completely prevented liver damage in `alfpCre gp130 Y757F/LoxP` mice, while all `alfpCre gp130 ΔSTAT/LoxP` mice died within 8 hours after Con A regardless of IL-6, versus 100% survival in the Y757F group.
- Gene array analysis identified KC and SAA2 as differentially IL-6–gp130-STAT3–regulated genes. Recombinant SAA (0.8 mg/kg) significantly reduced AST increases, and recombinant KC (40 µg/kg) significantly reduced AST levels and led to 100% survival versus 70% in NaCl-treated animals.
- IL-6 treatment significantly reduced PMN infiltration 4 hours after Con A injection, and IL-6 stimulation induced KC serum levels by approximately 100-fold.
Methods
- Male BALB/c mice, 8–10 weeks old, were used. Hepatocyte-specific gp130 mutants were generated by crossing `alfpCre` mice with `gp130 LoxP`, `gp130 ΔSTAT/ΔSTAT`, or `gp130 Y757F/Y757F` mice. Con A hepatitis was induced with 32.5 mg/kg i.v.; IL-6 (200 µg/kg) was given i.p. 3 hours before Con A; recombinant SAA (0.8 mg/kg) or KC (40 µg/kg) was given i.v. 1 hour before Con A.
- Liver injury was quantified by serum AST; cytokine levels by ELISA; STAT1/STAT3/ERK activation by Western blot and immunofluorescence; PMN infiltration by H&E counts.
- Gene expression profiling used Affymetrix mouse genome GeneChips on pooled liver RNA from 3 mice per group treated with IL-6 or NaCl; primary hepatocytes were isolated by collagenase perfusion and stimulated with 200 ng/ml IL-6.
Limitations
- The paper does not state a limitations section. Evident from the text: all experiments are in mice using the Con A model, so human relevance remains extrapolative.
- Gene expression profiling used pooled RNA from 3 mice per group, limiting assessment of inter-individual variability.
- Some supporting observations are reported as “data not shown” (e.g., hepatic mRNA expression and KC-dependent PMN influx), so they cannot be independently verified from the paper.
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Claims the paper makes
38 Own result · 11 Own interpretation · 7 Partly supported · 4 Supported · 4 No full text of the sources · 3 Own method · 3 No basis given · 1 Supported so far · accuracy not yet measured
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Increasing evidence demonstrates that IL-6 has a protective role during liver injury.”
- Also stated in: § Introduction · p. 1 · plain
“IL-6 is a pleiotropic cytokine with beneficial effects for the liver. This cytokine promotes liver regeneration and protects against a multitude of liver-damaging influences such as alcohol and CCl4 intoxication (1-4).”
What the sources say
- Supportedcites [1] source
The Discussion (p. 1534) reports that IL-6 conferred almost complete protection against Con A-induced hepatitis in mice when administered at least three hours before disease induction. The paper also notes that IL-6 given after Con A injection increased liver-injury markers, so the protective role shown here depends on timing. (LLM, conf=0.90)
- Supportedcites [2] source
The Discussion reports that IL-6 treatment reduced CCl4-induced liver injury in mice, including mice with an intact IL-6 response. It also reports greater injury in IL-6-deficient mice, supporting the attributed protective role in the liver-injury model studied. (LLM, conf=0.93)
- Supportedcites [3] source
The Introduction states that IL-6 plays a protective role in the mouse concanavalin A liver-injury model when administered before injury. The Discussion also reports protection in several mouse models of liver-cell damage, while noting that protection in human liver disease remains unestablished. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [4] source
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Introduction · p. 1 · plain
Every source the paper cites for this claim was checked and supports it.
In the paper
“IL-6 activates intracellular pathways via the gp130 receptor.”
- Also stated in: § Introduction · p. 1 · boosted
“The initiated intracellular signaling is strictly dependent on the function of gp130 (19).”
What the sources say
- Supportedcites [19] Ishihara, 2002, Biochim. Biophys. Acta. source
Section 2 describes gp130 as the signal-transducing subunit of the IL-6 receptor complex and says IL-6 binding triggers its association with gp130. The same section identifies two major downstream pathways generated through gp130. (LLM, conf=0.94)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Introduction · p. 1 · boosted
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, KC alone is not sufficient for the activation of infiltrated cells, and high systemic KC levels lead to impaired PMN activation via desensitization of the PMN CXC-receptor 2 (46).”
What the sources say
- Supportedcites [46] source
The Summary (p. 2039) reports that N51/KC expression recruited neutrophils without inflammatory activation. The Discussion (p. 2046) further suggests that activation such as degranulation requires other inflammatory mediators, supporting the claim that KC alone is insufficient. (LLM, conf=0.90)
plain- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, KC alone is not sufficient for the activation of infiltrated cells, and high systemic KC levels lead to impaired PMN activation via desensitization of the PMN CXC-receptor 2 (46).”
What the sources say
- Partly supportedcites [46] sourceExperimental — accuracy not yet measured
The Discussion (p. 2046) says chronic N51/KC expression recruits neutrophils without inflammatory activation and suggests that activation such as degranulation requires other mediators. It does not report that high systemic KC impairs PMN activation or that CXC-receptor 2 desensitization causes such impairment. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Earlier studies demonstrated that IL-6 attenuated liver injury in Con A-induced hepatitis (1).”
What the sources say
- Partly supportedcites [1] sourceExperimental — accuracy not yet measured
The Results (p. 1533) show that recombinant IL-6 given before Con A injection protected mice from liver injury. The timing qualification matters: IL-6 given at the same time had no protective effect, and administration afterward increased injury. The unqualified claim therefore overstates the finding. (LLM, conf=0.86)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrated that IL-6-gp130-dependent pathways in hepatocytes alone are sufficient for triggering protection in Con A-induced hepatitis.”
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“gp130-STAT3 signaling in hepatocytes mediates the IL-6-triggered protective effect.”
- Also stated in: § Figure 3 · p. 4 · plain
“IL-6 pretreatment of alfpCre gp130 Y757F/LoxP mice resulted in complete prevention of liver cell damage (Figure 5A). In contrast, alfpCre gp130 Δ STAT/LoxP animals showed enhanced sensitivity toward Con A when compared to wild-type mice (Figure 5B).”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Figure 3 · p. 4 · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The mouse IL-8 ortholog KC (also known as Groα ) and serum amyloid A2 (SAA2) was identified as differentially IL-6-gp130-STAT3-regulated genes.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-6-treated mice showed a significant reduction in PMN infiltration during Con Ainduced hepatitis (Figure 7D).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-6 serum concentrations correlated with survival rates.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“SAA2 showed the most prominent regulation.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Serum KC expression was also strictly dependent on an intact IL-6-gp130-STAT3-signaling axis in hepatocytes (Figures 6 and 7C).”
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Additionally, KC treatment leads to 100% survival during Con A-induced hepatitis compared with 70% in NaCL-treated animals.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The analysis of SAA serum expression showed that pronounced transcriptional induction of the saa gene strictly depended on IL-6-gp130-STAT3 signaling in hepatocytes.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Results of the gene expression analysis are remarkable in this context, as the CXC chemokine KC was strongly upregulated in response to activation of the IL-6gp130-STAT3 pathway.”
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“KC had a protective effect on Con A-induced T cell-mediated liver failure. The increase in transaminases was significantly blocked in the animals treated with KC (Figure 7E).”
- Also stated in: § The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1 · plain
“treatment with recombinant KC or serum SAA2 effectively reduced liver injury during Con A-induced hepatitis.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1 · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Lack of STAT3 activation in hepatocytes at these time points, as observed in alfpCre gp130 LoxP/LoxP (Figure 1B) and alfpCre gp130 Δ STAT/LoxP (Figure 5B) animals, correlated with poor prognosis.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In agreement with these findings, we demonstrated that activation of STAT3 is transitional.”
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“IL-6 treatment resulted in a significant reduction of PMN infiltration 4 hours after Con A injection (Figure 7D).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, when gp130 was selectively deleted in hepatocytes, IL-6 no longer conferred a protective effect (Figure 1).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Four hours after Con A injection, STAT3 activation occurred predominately in hepatocytes in a gp130-dependent manner (Figure 3, B and D).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“IL-6 pretreatment inhibited the increase of STAT3 activation in hepatocytes of wild-type mice, probably by inducing negative feedback mechanisms, e.g., induction of SOCS-3 in hepatocytes (Figure 6).”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Functional inactivation of this molecule in hepatocytes resulted in lack of signal activation after stimulation with ligands of the IL-6 cytokine family, e.g., IL-6 or OSM.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“treatment with recombinant KC or serum SAA2 effectively reduced liver injury during Con A-induced hepatitis.”
- Also stated in: § Figure 4 · p. 5 · hedged
“SAA injection resulted in a significant reduction in the increase of AST levels compared with those in vehicle-treated control animals, indicating that SAA may have a protective effect for Con Ainduced liver damage (Figure 7B).”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Figure 4 · p. 5 · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-6 pretreatment increased the amount of phosphorylated STAT3 in nonparenchymal cells 2 hours after Con A injection by increasing numbers of P-STAT3-positive cells (Figure 3C).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“IL-6 pretreatment of alfpCre gp130 Y757F/LoxP mice resulted in complete prevention of liver cell damage (Figure 5A).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“STAT3 activation 2 hours after Con A injection occurred predominantly in activated immune cells, such as NK cells and infiltrating monocytes (CD11b + cells) (Figure 3C, NaCl-treated groups).”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Strong STAT3 activation in this phase correlated with maximal IL-6 serum levels (Figure 2E).”
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Our present analysis shows that KC confers protection in Con Ainduced T cell-mediated hepatitis.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The IL-6 -gp130-dependent activation of STAT3 in wild-type mice is suppressed in alfpCre gp130 LoxP/LoxP animals .”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Indeed, treatment with recombinant SAA2 attenuated Con A-induced liver injury (Figure 7B).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“IL-6 stimulation of alfpCre gp130 Δ STAT/LoxP and alfpCre gp130 Y757F/LoxP animals revealed that phosphorylation of the 4 membrane distal tyrosine residues in gp130 that mediate activation of STAT3 are required to attenuate Con A-induced liver injury”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast, IL-6-induced activation of STAT3 in hepatocytes prior to or 4 hours after Con A challenge was associated with survival of the animals.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“SAA injection resulted in a significant reduction in the increase of AST levels compared with those in vehicle-treated control animals, indicating that SAA may have a protective effect for Con Ainduced liver damage (Figure 7B).”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Increased STAT3 activation 4 hours after Con A injection depended on gp130 expression in hepatocytes.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“while the gp130-SHP2-RAS-MAPK pathway appears to be completely dispensable in mediating this effect.”
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“But IL-6-dependent hepatic KC expression by itself induces no influx of PMNs in the liver (data not shown).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, in hepatocyte-specific gp130 knockout mice, Con A-induced liver injury was more pronounced and resulted in death of the animals within 24 hours, indicating that gp130-dependent pathways in liver cells are also protective in the later phase of Con A-induced liver injury.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These results indicate that a change in TNFα serum levels is not essential for the protective effect mediated by IL-6.”
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Additionally, we identified the IL-6-gp130-STAT3-dependent proteins KC and SAA2 as new candidates for therapeutic targets in liver diseases.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Further experiments in hepatocyte-specific knockout animals showed that lack of gp130 expression in hepatocytes renders these animals more susceptible to injury during various pathophysiological conditions of the liver (25).”
What the sources say
- Not checked — no full text of the sourcecites [25] source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Hepatic expression of KC and SAA2 mediate the liver-protective potential of IL-6, since treatment with recombinant KC or serum SAA2 effectively reduced liver injury during Con A-induced hepatitis.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, our findings indicate that the protective effects are mediated by STAT3.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results indicate that high systemic KC levels directly attenuate immune cell activation, most likely via modulating PMN function.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In conclusion, our present analysis suggests that IL-6-gp130dependent gene activation in hepatocytes confers protection against T cell hepatitis induced by Con A.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 14
- It may state two separate claims as one. 15
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The phosphorylation of gp130 leads to dimerization of gp130 and activation of STAT1 and STAT3 as well as the SHP2-RAS-MAPK pathway (where SHP2 is Src homology 2 [SH2] domain-containing protein tyrosine phosphatase) (20-22).”
What the sources say
- Not checked — no full text of the sourcecites [20] source
- Partly supportedcites [21] Nakajima, 1996, EMBO J. sourceExperimental — accuracy not yet measured
The Abstract describes IL-6-induced Stat activation, particularly Stat3, in M1 leukemia cells. The available passages do not establish that gp130 phosphorylation causes gp130 dimerization or activates STAT1 and the SHP2–RAS–MAPK pathway; those parts of the attributed claim are unsupported. (LLM, conf=0.78)
- Not checked — no full text of the sourcecites [22] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For signal transduction, IL-6 binds the membrane-bound IL-6 receptor α (gp80). The IL-6-gp80 dimer interacts with gp130, the signal transducing unit in this complex.”
What the sources say
- Partly supportedcites [19] Ishihara, 2002, Biochim. Biophys. Acta. sourceExperimental — accuracy not yet measured
Section 2 (page unavailable) says IL-6 binds IL-6Rα, triggering its association with gp130, which the paper identifies as the signal-transducing subunit. The paper distinguishes cell-expressed IL-6Rα from its soluble form, but the available passages do not identify IL-6Rα as “gp80”; that specific label is unsupported by our copy. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Activation of PMNs during Con A-induced liver failure is an essential step for disease progression (12).”
What the sources say
- Partly supportedcites [12] Bonder, 2004, J. Immunol. sourceExperimental — accuracy not yet measured
The Discussion (page not provided) says Con A activates neutrophils and calls their activation an important step in Con A-induced hepatitis. It describes neutrophil recruitment as paramount and shows that depletion prevents liver injury, but it does not establish that activation itself is essential. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Additionally, recent reports demonstrated that other IL-6 family members, e.g., IL-11 and CT-1, also confer protection in this model (35, 36).”
What the sources say
- Supportedcites [35] source
The cited paper supports the CT-1 example in the sentence. In “Treatment With AdCT-1 Protects Mice From Liver Damage Induced by Concanavalin A,” it reports that CT-1 treatment reduced liver injury in mice challenged with Con-A. The separate IL-11 example is not attributed to this source. (LLM, conf=0.94)
- Partly supportedcites [36] Mahboubi, 2000, J. Immunol. sourceExperimental — accuracy not yet measured
The Abstract identifies IL-11 as an IL-6-family cytokine, and the section on CTL- and complement-mediated cytolysis reports that IL-11 partially protects human endothelial cells from immune-mediated injury. The paper does not report protection by IL-11 or CT-1 in Con A-induced hepatitis; its experiments concern endothelial cells, not that hepatitis model. (LLM, conf=0.84)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“During the early stages, TNFα and IFNγ directly mediate liver cell damage (11).”
What the sources say
- Partly supportedcites [11] sourceExperimental — accuracy not yet measured
The introduction (page not supplied) reports that TNF levels rise early after Con A injection and that anti-TNF treatment blocks liver injury. The Discussion (page not supplied) says IFNγ is critical for apoptosis but finds no clear evidence that it directly induces it; the authors consider it more likely to modulate TNF-triggered pathways. Thus, the claim that both cytokines directly mediate early liver cell damage overstates the source. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Gp130 is the common signal transducer used by the IL-6 family of cytokines, which includes IL-6, leukemia inhibitory factor (LIF), IL-11, cardiotrophin-1 (CT-1), oncostatin-M (OSM), and the ciliary neurotrophic factor (19).”
What the sources say
- Supportedcites [19] Ishihara, 2002, Biochim. Biophys. Acta. source
Section 2, “Cell specificity at the level of the cytokine receptor” (page not provided), calls gp130 a common signal-transducing subunit of IL-6-family cytokine receptors. It also lists gp130 as shared by the receptors for CNTF, LIF, OSM, IL-11, and CT-1. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Additionally, recent studies showed effects of KC expression on monocyte recruitment during development of experimental atherosclerosis (47).”
What the sources say
- Supportedcites [47] Huo, 2001, J. Clin. Invest. source
The Discussion reports that KC is expressed on early atherosclerotic endothelium and significantly contributes to monocyte arrest. In the experimental apoE-deficient mouse artery model, blocking KC reduced monocyte accumulation, while adding KC increased it (Discussion, p. 1312; results, p. 1310). (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“High IL-6 serum concentrations after Con A injection were detectable in animals with a disruption of the IL-6gp130-STAT3 pathway and correlated with increased morbidity.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Hepatocytes of IL-6-pretreated wild-type mice showed STAT3 activation 3 hours after IL-6 injection. Up to 4 hours after initiation of Con A-induced hepatitis, these cells were not able to activate STAT3, although high IL-6 serum levels were detectable (Figures 3D and 2E).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, alfpCre gp130 Δ STAT/LoxP animals showed enhanced sensitivity toward Con A when compared to wild-type mice (Figure 5B). Independently of IL-6 pretreatment, all alfpCre gp130 Δ STAT/LoxP mice died within 8 hours after Con A injection in contrast to a 100% survival rate for all analyzed alfpCre gp130 Y757F/LoxP animals.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IFNγ levels in alfpCre gp130 Y757F/LoxP and wild-type mice were not affected by pretreatment with IL-6, despite our observation that both strains showed protection from Con A-induced liver damage (Figure 2, C and D; Figure 5, C and D).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-6 pretreatment completely blocked liver cell damage. No increase in transaminases was evident (Figure 1A).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-6 stimulation induces KC serum levels by approximately 100-fold, correlating with a pronounced upregulating of KC mRNA in the liver (Figure 6).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Figure 6 depicts a selection of genes that are significantly regulated by gp130-dependent pathways in hepatocytes in vivo.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In wild-type mice, TNFα levels were reduced after IL-6 stimulation. But in alfpCre gp130 Y757F/LoxP mice, which retained sensitivity to IL-6-dependent liver protection, no changes in TNFα levels were detected.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, all alfpCre gp130 LoxP/LoxP mice died within the first 20 hours after Con A injection. In contrast, all NaCL- and IL-6-treated wild-type animals survived during this phase, indicating a higher sensitivity of alfpCre gp130 LoxP/LoxP mice toward Con A.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It has been shown that SOCS-3 negatively regulates IL-6 signaling in vivo (43).”
What the sources say
- Not checked — no full text of the sourcecites [43] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The increased number of STAT3-positive cells likely reflects IL-6induced sensitization of NK cells, monocytes, or Kupffer cells to STAT3-activating pathways.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Con A-induced liver damage is a well-defined experimental animal model of acute hepatitis. It mimics human viral and autoimmune hepatitis in many aspects (8-10).”
What the sources say
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-6 pretreatment inhibited the increase of STAT3 activation in hepatocytes of wild-type mice, probably by inducing negative feedback mechanisms, e.g., induction of SOCS-3 in hepatocytes (Figure 6).”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A variety of factors, such as LPS or PDGF, induce tissue-specific expression of KC (45), which in turn promotes localized PMN migration.”
What the sources say
- Not checked — no full text of the sourcecites [45] Bozic, 1995, J. Immunol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, serum levels of TNFα and IFNγ showed no correlation with the capacity of IL-6 to provide protection from liver damage, indicating that alterations in concentrations of these cytokines are unlikely to explain protection.”
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To verify equal loading of protein samples, a Coomassie-blue stained SDS Gel was quantified.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both proteins are potent inhibitors of Con Ainduced hepatitis and might also be of interest in the treatment of immune-mediated liver diseases in humans.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, nuclear proteins were isolated from each liver, and the activation of STAT3 and ERK1/2 was analyzed by Western blot to verify the integrity of IL-6 signaling in each mouse.”
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To ensure that infiltrated cells in livers of Con A-treated mice were not eliminated, we washed the organs intensively by shaking the organs for 15 minutes in cold PBS.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The overall extent of hepatic gp130 inactivation in alfpCre gp130 LoxP/LoxP mice reflects complete gp130 deletion in hepatocytes.
“Since nonparenchymal cells show no gp130 deletion, the overall extent of hepatic gp130 inactivation is likely to reflect complete gp130 deletion in hepatocytes.”
The paper relies on this without support.
KC controls chemotaxis and activation of polymorph nuclear cells (PMNs) in areas of inflammation.
“KC controls chemotaxis and activation of polymorph nuclear cells (PMNs) in areas of inflammation.”
The paper relies on this without support.
SAA2 is a target of MMP.
“SAA2 is a known target of MMP and MMP activity induced during T cell-mediated hepatitis.”
The paper relies on this without support.
KC is an immediate early gene with low or no detectable expression in most tissues.
“KC is an immediate early gene with low or no detectable expression in most tissues.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“binding to its receptor has been shown to protect hepatocytes during acute hepatic injury [11]”
From Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli (2014) · cites this paper as [11]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Importantly, this indicates that under the appropriate circumstances, regulation of the endogenous hepatocellular IL-6 receptor can be autocrine instead of endrocrine/paracrine [11].”
From Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli (2014) · cites this paper as [11]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1
“The mouse IL-8 ortholog KC (also known as Groα )”
§ Introduction · p. 1
“KC, keratinocyte growth factor”
Citations
Cites
Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway
HEINRICH, P. C., BEHRMANN, I., MÜLLER-NEWEN, G., SCHAPER, F., & GRAEVE, L. (1998) · Biochemical Journal · doi:10.1042/bj3340297 · Cited by 2,130
gp 130 AND THE INTERLEUKIN-6 FAMILY OF CYTOKINES
Taga, T., & Kishimoto, T. (1997) · Annual Review of Immunology · doi:10.1146/annurev.immunol.15.1.797 · Cited by 1,468
Stahl, N., Farruggella, T. J., Boulton, T. G., Zhong, Z., Darnell, J. E., & Yancopoulos, G. D. (1995) · Science · doi:10.1126/science.7871433 · Cited by 979
SOCS3 negatively regulates IL-6 signaling in vivo
Croker, B. A., Krebs, D. L., Zhang, J.-G., Wormald, S., Willson, T. A., Stanley, E. G., Robb, L., Greenhalgh, C. J., Förster, I., Clausen, B. E., et al. (2003) · Nature Immunology · doi:10.1038/ni931 · Cited by 840
Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver
Jaeschke, H., & Farhood, A. I. (1991) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1991.260.3.g355 · Cited by 662
Fukada, T., Hibi, M., Yamanaka, Y., Takahashi-Tezuka, M., Fujitani, Y., Yamaguchi, T., Nakajima, K., & Hirano, T. (1996) · Immunity · doi:10.1016/s1074-7613(00)80501-4 · Cited by 652
Nakajima, K., Yamanaka, Y., Nakae, K., Kojima, H., Ichiba, M., Kiuchi, N., Kitaoka, T., Fukada, T., Hibi, M., & Hirano, T. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00734.x · Cited by 565
Mizuhara, H., O'Neill, E., Seki, N., Ogawa, T., Kusunoki, C., Otsuka, K., Satoh, S., Niwa, M., Senoh, H., & Fujiwara, H. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.179.5.1529 · Cited by 517
Concanavalin A?induced T-cell?Mediated hepatic injury in mice: The role of tumor necrosis factor*1
Gantner, F. (1995) · Hepatology · doi:10.1016/0270-9139(95)90428-x · Cited by 487
Tebbutt, N. C., Giraud, A. S., Inglese, M., Jenkins, B., Waring, P., Clay, F. J., Malki, S., Alderman, B. M., Grail, D., Hollande, F., et al. (2002) · Nature Medicine · doi:10.1038/nm763 · Cited by 474
Self-citation
Research works printed but not linked: 1
- Gantner, 1995, Hepatology., 21, 190
Cited by
Sorted by citations
Fausto, N., Campbell, J. S., & Riehle, K. J. (2006) · Hepatology · doi:10.1002/hep.20969 · Cited by 1,378
Living in the liver: hepatic infections
Protzer, U., Maini, M. K., & Knolle, P. A. (2012) · Nature reviews. Immunology · doi:10.1038/nri3169 · Cited by 577
Tan, C. Y., Lai, R. C., Wong, W., Dan, Y. Y., Lim, S.-K., & Ho, H. K. (2014) · Stem Cell Research & Therapy · doi:10.1186/scrt465 · Cited by 548
Inflammatory Pathways in Liver Homeostasis and Liver Injury
Tacke, F., Luedde, T., & Trautwein, C. (2009) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-008-8091-0 · Cited by 393
Self-citationThe importance of immune dysfunction in determining outcome in acute liver failure
Antoniades, C. G., Berry, P., Wendon, J. A., & Vergani, D. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.08.009 · Cited by 364
Metadata
- Authors
- Klein, C., Wüstefeld, T., Assmus, U., Roskams, T., Rose-John, S., Müller, M., Manns, M. P., Ernst, M., & Trautwein, C.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- KU Leuven (BE)
- Wageningen University & Research (NL)
- The Royal Melbourne Hospital (AU)
- Venue
- Journal of Clinical Investigation
- Published
- 2005-03-03
- Volume
- 115
- Issue
- 4
- Pages
- 860-869
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2020798985
- Cited by
- 200
- References
- 52
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 11 · 2020: 9 · 2019: 7 · 2018: 7 · 2017: 10 · 2016: 5 · 2015: 8 · 2014: 12 · 2013: 15 · 2012: 12
- FWCI
- 4.80
- Type
- journal article
- Language
- en
- Open access
- green
- research.wur.nl
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- PubMed Central (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 566, Project B8)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- interleukin-6, gp130, STAT3, hepatocytes, liver injury, immune-mediated hepatitis, concanavalin A-induced hepatitis, hepatoprotection, SAA2, STAT1, hepatocyte-specific knockout mice, therapeutic target
- MeSH terms
- Serum Amyloid A Protein, Animals, Concanavalin A, DNA-Binding Proteins, Enzyme Activation, Hepatitis, Interferon-gamma, Liver, Male, Membrane Glycoproteins, Mice, Inbred BALB C, T-Lymphocytes, Tumor Necrosis Factor-alpha, Signal Transduction, Trans-Activators, Antigens, CD, Interleukin-6, Mice, Knockout, Gene Expression Profiling, Hepatocytes, Extracellular Signal-Regulated MAP Kinases, STAT1 Transcription Factor, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-23, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-23 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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