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.
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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.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
15 of 24 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured
- Premisecitation§ The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1
IL-6 has a protective role during liver injury.
“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).”
Quote in the paperSubstantial claim3 of 4 sources checked - Also stated in: § Introduction · p. 1 · plain
- Premisecitation§ The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1
IL-6 activates intracellular pathways via the gp130 receptor.
“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).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [19] Ishihara, 2002, Biochim. Biophys. Acta. source
- Also stated in: § Introduction · p. 1 · boosted
- Premisecitation§ Figure 7 · p. 8
KC alone is not sufficient for the activation of infiltrated cells.
“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).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [46] source
- Premisecitation§ Figure 7 · p. 8
High systemic KC levels lead to impaired PMN activation via desensitization of the PMN CXC-receptor 2.
“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).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [46] source
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)
Experimental — accuracy not yet measured
- Premisecitation§ Figure 5 · p. 6
IL-6 attenuates liver injury in Con A-induced hepatitis.
“Earlier studies demonstrated that IL-6 attenuated liver injury in Con A-induced hepatitis (1).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] source
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)
Experimental — accuracy not yet measured
- Findingown data§ The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1
IL-6-gp130-dependent pathways in hepatocytes alone are sufficient for triggering protection in Con A-induced hepatitis.
“We demonstrated that IL-6-gp130-dependent pathways in hepatocytes alone are sufficient for triggering protection in Con A-induced hepatitis.”
Quote in the paperSubstantial claim - Findingown data§ The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1
gp130-STAT3 signaling in hepatocytes mediates the IL-6-triggered protective effect.
“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).”
Quote in the paperSubstantial claim - Also stated in: § Figure 3 · p. 4 · plain
- Findingown data§ The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1
KC and SAA2 are differentially IL-6-gp130-STAT3-regulated genes.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Figure 7 · p. 8
IL-6-treated mice show a significant reduction in PMN infiltration during Con A-induced hepatitis.
“IL-6-treated mice showed a significant reduction in PMN infiltration during Con Ainduced hepatitis (Figure 7D).”
Quote in the paperSubstantial claim - Findingown data§ Figure 6 · p. 7
IL-6 serum concentrations correlate with survival rates.
“IL-6 serum concentrations correlated with survival rates.”
Quote in the paperNot a substantial claim - Findingown data§ Figure 7 · p. 8
SAA2 shows the most prominent regulation among the acute phase genes regulated via IL-6-gp130-STAT3.
“SAA2 showed the most prominent regulation.”
Quote in the paperSubstantial claim - Findingown data§ Figure 4 · p. 5
Serum KC expression is strictly dependent on an intact IL-6-gp130-STAT3-signaling axis in hepatocytes.
“Serum KC expression was also strictly dependent on an intact IL-6-gp130-STAT3-signaling axis in hepatocytes (Figures 6 and 7C).”
Quote in the paperSubstantial claim - Findingown data§ Figure 4 · p. 5
KC treatment leads to 100% survival during Con A-induced hepatitis compared with 70% in NaCl-treated animals.
“Additionally, KC treatment leads to 100% survival during Con A-induced hepatitis compared with 70% in NaCL-treated animals.”
Quote in the paperSubstantial claim - Findingown data§ Figure 4 · p. 5
Pronounced transcriptional induction of the saa gene strictly depends on IL-6-gp130-STAT3 signaling in hepatocytes.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Figure 7 · p. 8
The CXC chemokine KC is strongly upregulated in response to activation of the IL-6-gp130-STAT3 pathway.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Figure 4 · p. 5
Treatment with recombinant KC effectively reduces liver injury during Con A-induced hepatitis.
“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.”
Quote in the paperSubstantial claim - Also stated in: § The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1 · plain
- Findingown data§ Figure 6 · p. 7
Lack of STAT3 activation in hepatocytes at these time points, as observed in alfpCre gp130 LoxP/LoxP and alfpCre gp130 ΔSTAT/LoxP animals, correlates with poor prognosis.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Figure 6 · p. 7
Activation of STAT3 is transitional.
“In agreement with these findings, we demonstrated that activation of STAT3 is transitional.”
Quote in the paperNot a substantial claim - Findingown data§ Figure 4 · p. 5
IL-6 treatment results in a significant reduction of PMN infiltration 4 hours after Con A injection.
“IL-6 treatment resulted in a significant reduction of PMN infiltration 4 hours after Con A injection (Figure 7D).”
Quote in the paperSubstantial claim - Findingown data§ Figure 5 · p. 6
When gp130 is selectively deleted in hepatocytes, IL-6 no longer confers a protective effect.
“Interestingly, when gp130 was selectively deleted in hepatocytes, IL-6 no longer conferred a protective effect (Figure 1).”
Quote in the paperSubstantial claim - Findingown data§ Figure 6 · p. 7
Four hours after Con A injection, STAT3 activation occurs predominantly in hepatocytes in a gp130-dependent manner.
“Four hours after Con A injection, STAT3 activation occurred predominately in hepatocytes in a gp130-dependent manner (Figure 3, B and D).”
Quote in the paperSubstantial claim - Findingreasoning§ Figure 6 · p. 7
IL-6 pretreatment inhibits the increase of STAT3 activation in hepatocytes of wild-type mice.
“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).”
Quote in the paperNot a substantial claim - Findingown data§ Figure 5 · p. 6
Functional inactivation of gp130 in hepatocytes results in lack of signal activation after stimulation with ligands of the IL-6 cytokine family, e.g., IL-6 or OSM.
“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.”
Quote in the paperSubstantial claim - Findingown data§ The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1
Treatment with serum SAA2 effectively reduces liver injury during Con A-induced hepatitis.
“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).”
Quote in the paperSubstantial claim - Also stated in: § Figure 4 · p. 5 · hedged
- Findingown data§ Figure 6 · p. 7
IL-6 pretreatment increases the amount of phosphorylated STAT3 in nonparenchymal cells 2 hours after Con A injection by increasing numbers of P-STAT3-positive cells.
“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).”
Quote in the paperNot a substantial claim - Findingown data§ Figure 3 · p. 4
IL-6 pretreatment of alfpCre gp130 Y757F/LoxP mice results in complete prevention of liver cell damage.
“IL-6 pretreatment of alfpCre gp130 Y757F/LoxP mice resulted in complete prevention of liver cell damage (Figure 5A).”
Quote in the paperSubstantial claim - Findingown data§ Figure 6 · p. 7
STAT3 activation 2 hours after Con A injection occurs predominantly in activated immune cells, such as NK cells and infiltrating monocytes (CD11b+ cells).
“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).”
Quote in the paperNot a substantial claim - Findingown data§ Figure 6 · p. 7
Strong STAT3 activation in this phase correlates with maximal IL-6 serum levels.
“Strong STAT3 activation in this phase correlated with maximal IL-6 serum levels (Figure 2E).”
Quote in the paperNot a substantial claim - Findingreasoning§ Figure 7 · p. 8
KC confers protection in Con A-induced T cell-mediated hepatitis.
“Our present analysis shows that KC confers protection in Con Ainduced T cell-mediated hepatitis.”
Quote in the paperSubstantial claim - Findingnone given§ Results · p. 2
IL-6-gp130-dependent activation of STAT3 in wild-type mice is suppressed in alfpCre gp130 LoxP/LoxP animals.
“The IL-6 -gp130-dependent activation of STAT3 in wild-type mice is suppressed in alfpCre gp130 LoxP/LoxP animals .”
Quote in the paperSubstantial claim - Findingown data§ Figure 7 · p. 8
Treatment with recombinant SAA2 attenuates Con A-induced liver injury.
“Indeed, treatment with recombinant SAA2 attenuated Con A-induced liver injury (Figure 7B).”
Quote in the paperSubstantial claim - Findingown data§ Figure 6 · p. 7
Phosphorylation of the four membrane-distal tyrosine residues in gp130 that mediate STAT3 activation is required to attenuate Con A-induced liver injury.
“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”
Quote in the paperSubstantial claim - Findingown data§ Figure 6 · p. 7
IL-6-induced activation of STAT3 in hepatocytes prior to or 4 hours after Con A challenge is associated with survival of the animals.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Figure 4 · p. 5
SAA injection results in a significant reduction in the increase of AST levels compared with vehicle-treated control animals.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Figure 2 · p. 3
Increased STAT3 activation 4 hours after Con A injection depends on gp130 expression in hepatocytes.
“Increased STAT3 activation 4 hours after Con A injection depended on gp130 expression in hepatocytes.”
Quote in the paperSubstantial claim - Findingown data§ Figure 6 · p. 7
The gp130-SHP2-RAS-MAPK pathway is completely dispensable for mediating IL-6-dependent protection against Con A-induced liver injury.
“while the gp130-SHP2-RAS-MAPK pathway appears to be completely dispensable in mediating this effect.”
Quote in the paperSubstantial claim - Findingown data§ Figure 7 · p. 8
IL-6-dependent hepatic KC expression by itself induces no influx of PMNs in the liver.
“But IL-6-dependent hepatic KC expression by itself induces no influx of PMNs in the liver (data not shown).”
Quote in the paperSubstantial claim - Interpretationown data§ Figure 5 · p. 6
gp130-dependent pathways in liver cells are also protective in the later phase of Con A-induced liver injury.
“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.”
Quote in the paperSubstantial claim - Interpretationown data§ Figure 6 · p. 7
A change in TNFα serum levels is not essential for the protective effect mediated by IL-6.
“These results indicate that a change in TNFα serum levels is not essential for the protective effect mediated by IL-6.”
Quote in the paperSubstantial claim - Interpretationown data§ The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1
KC and SAA2 are new candidates for therapeutic targets in liver diseases.
“Additionally, we identified the IL-6-gp130-STAT3-dependent proteins KC and SAA2 as new candidates for therapeutic targets in liver diseases.”
Quote in the paperSubstantial claim - Premisecitation§ Figure 5 · p. 6
Lack of gp130 expression in hepatocytes renders animals more susceptible to injury during various pathophysiological conditions of the liver.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] source
- Interpretationown data§ The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury · p. 1
Hepatic expression of KC and SAA2 mediates the liver-protective potential of IL-6.
“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.”
Quote in the paperSubstantial claim - Interpretationown data§ Figure 6 · p. 7
The protective effects of IL-6 against Con A-induced liver injury are mediated by STAT3.
“Therefore, our findings indicate that the protective effects are mediated by STAT3.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Figure 7 · p. 8
High systemic KC levels directly attenuate immune cell activation, most likely via modulating PMN function.
“These results indicate that high systemic KC levels directly attenuate immune cell activation, most likely via modulating PMN function.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Figure 7 · p. 8
IL-6-gp130-dependent gene activation in hepatocytes confers protection against T cell hepatitis induced by Con A.
“In conclusion, our present analysis suggests that IL-6-gp130dependent gene activation in hepatocytes confers protection against T cell hepatitis induced by Con A.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 14
- May combine two claims. 15
- The quote only partly states this claim. 1
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ Introduction · p. 1Phosphorylation of gp130 leads to dimerization of gp130 and activation of STAT1 and STAT3 as well as the SHP2-RAS-MAPK pathway.
“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).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [20] source
- cites [21] Nakajima, 1996, EMBO J. source
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)
Experimental — accuracy not yet measured - cites [22] source
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ Introduction · p. 1IL-6 binds membrane-bound IL-6 receptor α (gp80), and the IL-6-gp80 dimer interacts with gp130, the signal transducing unit.
“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.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [19] Ishihara, 2002, Biochim. Biophys. Acta. source
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)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
Premisecitation§ Figure 7 · p. 8Activation of PMNs during Con A-induced liver failure is an essential step for disease progression.
“Activation of PMNs during Con A-induced liver failure is an essential step for disease progression (12).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [12] Bonder, 2004, J. Immunol. source
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)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Figure 5 · p. 6Other IL-6 family members, e.g., IL-11 and CT-1, also confer protection in Con A-induced hepatitis.
“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).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [35] source
- cites [36] Mahboubi, 2000, J. Immunol. source
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)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Introduction · p. 1During early stages of Con A-induced hepatitis, TNFα and IFNγ directly mediate liver cell damage.
“During the early stages, TNFα and IFNγ directly mediate liver cell damage (11).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [11] source
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)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
Premisecitation§ Introduction · p. 1gp130 is the common signal transducer used by the IL-6 family of cytokines.
“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).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [19] Ishihara, 2002, Biochim. Biophys. Acta. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Figure 7 · p. 8Recent studies showed effects of KC expression on monocyte recruitment during development of experimental atherosclerosis.
“Additionally, recent studies showed effects of KC expression on monocyte recruitment during development of experimental atherosclerosis (47).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [47] Huo, 2001, J. Clin. Invest. source
May combine two claims.
Findingown data§ Figure 6 · p. 7High IL-6 serum concentrations after Con A injection are detectable in animals with a disruption of the IL-6-gp130-STAT3 pathway and correlate with increased morbidity.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 6 · p. 7Hepatocytes of IL-6-pretreated wild-type mice show STAT3 activation 3 hours after IL-6 injection but are not able to activate STAT3 up to 4 hours after initiation of Con A-induced hepatitis, although high IL-6 serum levels are detectable.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 3 · p. 4alfpCre gp130 Δ STAT/LoxP animals show enhanced sensitivity toward Con A compared to wild-type mice, and all die within 8 hours after Con A injection independently of IL-6 pretreatment.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 6 · p. 7IFNγ levels in alfpCre gp130Y757F/LoxP and wild-type mice are not affected by pretreatment with IL-6, despite both strains showing protection from Con A-induced liver damage.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Results · p. 2IL-6 pretreatment completely blocks liver cell damage in gp130 wild-type mice, with no increase in transaminases.
“IL-6 pretreatment completely blocked liver cell damage. No increase in transaminases was evident (Figure 1A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 7 · p. 8IL-6 stimulation induces KC serum levels by approximately 100-fold, correlating with a pronounced upregulation of KC mRNA in the liver.
“IL-6 stimulation induces KC serum levels by approximately 100-fold, correlating with a pronounced upregulating of KC mRNA in the liver (Figure 6).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data§ Figure 3 · p. 4Hepatic gene expression profiles in IL-6-treated wild-type, alfpCre gp130 LoxP/LoxP, alfpCre gp130 Y757F/LoxP, and alfpCre gp130 Δ STAT/LoxP mice show genes significantly regulated by gp130-dependent pathways in hepatocytes in vivo.
“Figure 6 depicts a selection of genes that are significantly regulated by gp130-dependent pathways in hepatocytes in vivo.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 6 · p. 7IL-6 stimulation reduces TNFα levels in wild-type mice but does not change TNFα levels in alfpCre gp130Y757F/LoxP mice.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 1 · p. 2All alfpCre gp130 LoxP/LoxP mice died within the first 20 hours after Con A injection, whereas all NaCl- and IL-6-treated wild-type animals survived during this phase.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Figure 6 · p. 7SOCS-3 negatively regulates IL-6 signaling in vivo.
“It has been shown that SOCS-3 negatively regulates IL-6 signaling in vivo (43).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] source
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning§ Figure 6 · p. 7The increased number of STAT3-positive cells likely reflects IL-6-induced sensitization of NK cells, monocytes, or Kupffer cells to STAT3-activating pathways.
“The increased number of STAT3-positive cells likely reflects IL-6induced sensitization of NK cells, monocytes, or Kupffer cells to STAT3-activating pathways.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Premisecitation§ Introduction · p. 1Con A-induced liver damage is a well-defined experimental animal model of acute hepatitis that mimics human viral and autoimmune hepatitis in many aspects.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Interpretationreasoning§ Figure 6 · p. 7IL-6 pretreatment inhibits the increase of STAT3 activation in hepatocytes of wild-type mice probably by inducing negative feedback mechanisms, such as induction of SOCS-3 in hepatocytes.
“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).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Figure 7 · p. 8A variety of factors, such as LPS or PDGF, induce tissue-specific expression of KC, which in turn promotes localized PMN migration.
“A variety of factors, such as LPS or PDGF, induce tissue-specific expression of KC (45), which in turn promotes localized PMN migration.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Bozic, 1995, J. Immunol. source
May combine two claims.
Interpretationown data§ Figure 6 · p. 7Serum levels of TNFα and IFNγ show 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.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given§ Detection of nuclear p-STAT3, p-STAT1, and p-ERK · p. 9To verify equal loading of protein samples, a Coomassie-blue stained SDS Gel was quantified.
“To verify equal loading of protein samples, a Coomassie-blue stained SDS Gel was quantified.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown data§ research article · p. 9Both SAA2 and KC are potent inhibitors of Con A-induced hepatitis.
“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.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown data§ Gene expression profile analysis · p. 9Nuclear proteins were isolated from each liver, and activation of STAT3 and ERK1/2 was analyzed by Western blot to verify the integrity of IL-6 signaling in each mouse.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given§ IL-6, SAA, KC, and Con A treatment · p. 9To ensure that infiltrated cells in livers of Con A-treated mice were not eliminated, the organs were washed intensively by shaking for 15 minutes in cold PBS.
“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.”
Quote in the paperNot a substantial claim
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?
Binding of IL-6 to its receptor protects hepatocytes during acute hepatic injury.
“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]
Under appropriate circumstances, regulation of the endogenous hepatocellular IL-6 receptor can be autocrine instead of endocrine/paracrine.
“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]
The Introduction (p. 1) describes IL-6 binding the hepatocyte IL-6 receptor and signaling through gp130, but does not identify the source of IL-6. A search for autocrine signaling and hepatocyte production of IL-6 found no passage establishing that receptor regulation can be autocrine rather than endocrine or paracrine. (LLM, conf=0.72)
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.
KC is identified as both Groα and keratinocyte growth factor
MinorThe paper identifies KC as the mouse IL-8 ortholog Groα, but its abbreviations list defines KC as keratinocyte growth factor. These are different names for different factors.
“The mouse IL-8 ortholog KC (also known as Groα )”
“KC, keratinocyte growth factor”
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- 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
- Health Sciences › Medicine › Oncology › 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
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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.
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