Interleukin 6 Is Important for Survival After Partial Hepatectomy in Mice
Open accessAbstract
The response to partial hepatectomy (PH) is impaired in interleukin 6 (IL–6)–deficient mice. IL–6 is well known for its role in the induction of the acute phase (AP) response, and the impairment of this response after surgery and hepatectomy could explain the defective hepatocyte regeneration. In addition, it was proposed that IL–6 has an important role in stimulating the reentry of quiescent cells into the cell cycle within the first 2 to 4 hours after PH. To further analyze the role for IL–6, we performed two third hepatectomies in wild–type mice, in IL–6 knockout (KO) mice, and in IL–6 KO mice that were treated 30 minutes before surgery with intravenous (IV) (short acting) or subcutaneous (SC) (long acting) injections of recombinant IL–6. The high postoperative mortality of IL–6–deficient mice could be completely prevented by SC, but not by IV IL–6 treatment, showing the requirement of a sustained action of IL–6. However, there is a subset of IL–6 KO mice that survives a PH in good health even without IL–6 treatment. When we analyzed these mice, we found an intact liver regeneration and no indication of a block in cell cycle reentry. We conclude that the major role of IL–6 is the induction of an adaptive response to PH that ensures body homeostasis and survival.
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Written from the paper’s full text.
TL;DR
In IL-6-deficient mice, partial hepatectomy causes high mortality that can be rescued by subcutaneous but not intravenous IL-6, indicating that sustained IL-6/STAT3-dependent acute-phase signaling is required for survival. Surviving IL-6 knockout mice still regenerate liver mass through hepatocyte proliferation, with delayed cyclin D1/c-myc induction and compensatory cell-cycle mechanisms.
Key findings
- Seven-day survival after partial hepatectomy was 86% in wild-type controls versus 17% in untreated IL-6 knockout mice; subcutaneous IL-6 restored survival to 86%, whereas intravenous IL-6 did not rescue survival.
- Subcutaneous IL-6 produced later peak serum concentrations and prolonged STAT3 activation, and induced the acute-phase protein SAP; intravenous IL-6 did not induce SAP above constitutive levels.
- In IL-6 knockout mice that survived in good health, liver mass restoration was similar to wild-type mice; BrdU incorporation was lower at 40 hours after PH (17% vs. 27% nuclei stained) but not different at 48 or 60 hours.
- Cyclin D1 and c-myc up-regulation were absent early in IL-6 knockout livers, but cyclin E-CDK2 association was unchanged and cyclin D3-CDK6 lacked the inhibitor p27^Kip1 at 36 and 48 hours, suggesting compensatory cell-cycle progression.
Methods
- Eight- to 12-week-old IL-6-deficient mice and C57Bl/6J controls underwent two-thirds partial hepatectomy; IL-6 knockout mice received 500 ng/g body weight recombinant human IL-6 subcutaneously or intravenously 30 minutes before surgery.
- Survival was observed for 7 days; liver regeneration was assessed by liver weight, hepatocyte counts, and in vivo BrdU labeling at time points after PH.
- Molecular analyses included serum IL-6 ELISA, STAT3 electrophoretic mobility shift assay, Northern and Western blots for SAP, and Western blot/immunoprecipitation for cyclins D1/D2/D3, c-myc, CDK2/CDK6, and p27.
Limitations
- The paper states that loss-of-function models such as IL-6-deficient mice cannot distinguish between different functions of a cytokine because all functions are lost simultaneously.
- The paper notes that its BrdU results differ from prior work possibly because it excluded sick mice from regeneration analysis or because of different mouse strains.
- Evident from the text: regeneration and cell-cycle analyses were restricted to the subset of IL-6 knockout mice that survived in good health, while sick mice were euthanized and excluded, so findings may not represent all IL-6-deficient mice after PH.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
2 of 23 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Other D type cyclins can functionally replace cyclin D1 in most tissues.
“From experiments with cyclin D1 KO mice, it is known that other D type cyclins can functionally replace cyclin D1 in most tissues.17,18”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [17] Sicinski, 1995, Cell source
- cites [18] Fantl, 1995, Genes Dev source
The Discussion (page not provided) proposes that D-type cyclins might substitute for one another, but also offers alternative signaling pathways as an explanation and says further experiments are needed to distinguish them. It therefore does not establish that other D-type cyclins functionally replace cyclin D1 in most tissues. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
Similar results (no significant difference in remnant liver growth) have been reported with a different strain of IL-6-deficient mice.
“Simi-lar results have been reported with a different strain of IL-6 -deficient mice.16”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [16] Sakamoto, 1999, Hepatology source
The “Sequential Liver Weight Before and After PH” section reports that liver-weight recovery was significantly impaired in IL-6-deficient mice at 48, 60, and 72 hours. The groups reached the same percentage of normal liver weight by 96 hours, so the claim holds for that endpoint but not for remnant liver growth throughout recovery. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Findingown data
In IL-6 KO mice that survive partial hepatectomy, liver regeneration is intact.
“When we analyzed these mice, we found an intact liver regeneration and no indication of a block in cell cycle reentry.”
- Also stated in: § Abstract · plain
“Contrary to previously published results, we do not find a significant inhibition of hepatocyte proliferation in those IL-6deficient mice that survive PH.”
- Also stated in: § Liver Regeneration in IL-6 -Deficient Mice That Survive After PH. · plain
“Interestingly, IL-6 KO mice that survived in good health after PH showed a very similar regain of liver weight as controls (Fig. 3A).”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Also stated in: § Abstract · plain
- Findingown data
In IL-6 KO mice that survive partial hepatectomy, there is no indication of a block in cell cycle reentry.
“When we analyzed these mice, we found an intact liver regeneration and no indication of a block in cell cycle reentry.”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Findingown data
A subset of IL-6 KO mice survives partial hepatectomy in good health even without IL-6 treatment.
“However, there is a subset of IL-6 KO mice that survives a PH in good health even without IL-6 treatment.”
Quote in the paperSubstantial claim
- Findingown data
Induction of the acute-phase protein SAP is observed only after subcutaneous IL-6 treatment, not after intravenous IL-6 treatment.
“It is noteworthy that the induction of the AP protein SAP is observed only after SC, and not after IV IL-6 treatment.”
- Also stated in: § Discussion · plain
“Concentration of the AP protein SAP in the serum of mice after IV or SC injection of 500 ng/g bodyweight rhIL-6.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Serum SAP concentration was much more strongly up-regulated after subcutaneous than after intravenous injection of IL-6.
“In agreement with this, the serum concentration of SAP was much more strongly up-regulated in mice after SC than after IV injection of IL-6 (Fig. 2D).”
Quote in the paperNot a substantial claim - Findingown data
Survival during the 7 days after partial hepatectomy was 86% for wild-type controls and 17% for IL-6 KO mice not treated with IL-6.
“Survival during the 7 days after surgery was 86% for controls and 17% for KO mice not treated with IL-6 (Fig. 1).”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 knockout mice and wild-type controls are comparable except for the IL-6 deficiency, including their genetic background.
- Findingown data
Subcutaneous injection of recombinant human IL-6 strongly induced SAP mRNA 8 and 24 hours after injection in IL-6 KO mice.
“We found a strong induction of SAP 8 and 24 hours after SC injection of 500 ng/g bodyweight rhIL-6 in IL-6 KO mice.”
Quote in the paperSubstantial claim - Findingown data
In the subset of IL-6 KO mice that survive in good health after partial hepatectomy, liver regeneration takes place without the induction of cyclin D1.
“We show here, that in the subset of IL-6 KO mice that survive in good health after PH, liver regeneration takes place without the induction of cyclin D1.”
Quote in the paperSubstantial claim - Findingown data
In IL-6 KO mice after partial hepatectomy, induction of c-myc and cyclin D1 is impaired.
“From these studies it is known that the induction of cmyc and cyclin D1 is impaired in IL-6 -deficient mice, a finding that was confirmed in our study.”
- Also stated in: § Discussion · plain
“Cyclin D1 is not induced in IL-6 KO mice in the first 48 hours after PH.”
- Also stated in: § Discussion · plain
“Up-regulation of c-myc is lacking in IL-6 KO mice.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
In wild-type mice, cyclin D1 is up-regulated bimodally with maximal values at 36 and 72 hours after partial hepatectomy.
“In wild-type mice, cyclin D1 is up-regulated in a bimodal way with maximal values at 36 hours and 72 hours after PH, probably reflecting the G1 phases of the first and second round of hepatocyte cell cycling (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
In IL-6 KO mice that survive well after partial hepatectomy, remnant liver growth is not significantly different from wild-type mice.
“Surprisingly, we found no significant difference in the growth of the remnant liver in these mice compared with wild-type mice.”
- Also stated in: § Discussion · plain
“Both wild-type and IL-6 KO mice restored about 95% of the calculated liver weight within the first 7 days (see text for liver weight calculation).”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Hepatocyte nuclei count at 96 hours after partial hepatectomy was 328 ±26 (95% CI) in wild-type and 279 ±37 in IL-6 KO mice.
“We found 328 Ϯ 26 (95% CI) and 279 Ϯ 37 (95% CI) in wild-type and IL-6 KO mice, respectively (Fig. 3B).”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Findingown data
In wild-type mice, mean liver weight was 5.03% of body weight (95% CI ±0.092; n=14).
“In wild-type animals, we found a mean value of 5.03% of the bodyweight (95% CI, Ϯ 0.092; n ϭ 14).”
Quote in the paperNot a substantial claim - Findingown data
Cyclin E-CDK2 association during liver regeneration in IL-6 KO mice is not changed compared with wild-type mice.
“We tested the cyclin E-CDK2 association during liver regeneration in IL-6 KO mouse and found it not changed compared with wild-type mice (Fig. 5E).”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Findingown data
BrdU labeling showed significantly lower DNA synthesis in IL-6 KO mice at 40 hours after partial hepatectomy (17% vs 27% nuclei stained).
“A significant lower DNA synthesis rate was found in IL-6 KO mice at time point 40 hours after PH, when IL-6 KO had 17% of the nuclei stained with BrdU and wild-type mice 27%.”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Findingown data
Binding of the CDK inhibitor p27Kip1 to cyclin D3-CDK6 is lost specifically in IL-6 KO mice at 36 and 48 hours after partial hepatectomy.
“However, when we analyzed the proteins bound to cyclin D3, we found a stable association with the CDK6 in both wild-type and IL-6 KO mice in G0 and G1, but a loss of binding of the CDK inhibitor p27 Kip1 specifically in IL-6 KO mice at 36 hours and 48 hours after PH (Fig. 5D and 5E).”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Findingown data
In IL-6 KO mice during liver regeneration, the cyclin E-CDK2 complex is formed in the absence of cyclin D1.
“the cyclin E-CDK2 complex is formed in the absence of cyclin D1”
Quote in the paperSubstantial claim - Findingown data
IL-6 KO mice that survive partial hepatectomy in good health have restoration of liver mass similar or identical to controls.
“Interestingly, IL-6 KO mice that survived in good health after PH showed a very similar regain of liver weight as controls (Fig. 3A).”
- Also stated in: § Liver Regeneration in IL-6 -Deficient Mice That Survive After PH. · boosted
“In conclusion, IL-6 KO mice that survive a two-third hepatectomy have a restoration of their liver mass identical to control mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Also stated in: § Liver Regeneration in IL-6 -Deficient Mice That Survive After PH. · boosted
- Findingown data
Cyclin D3 is stably associated with CDK6 in both wild-type and IL-6 KO mice in G0 and G1.
“However, when we analyzed the proteins bound to cyclin D3, we found a stable association with the CDK6 in both wild-type and IL-6 KO mice in G0 and G1, but a loss of binding of the CDK inhibitor p27 Kip1 specifically in IL-6 KO mice at 36 hours and 48 hours after PH (Fig. 5D and 5E).”
Quote in the paperNot a substantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Findingown data
At 48 and 60 hours after partial hepatectomy, no differences in DNA synthesis could be detected between IL-6 KO and wild-type mice.
“However, at the later time points 48 hours and 60 hours, no differences could be detected any longer (Fig. 4B).”
Quote in the paperNot a substantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Findingown data
Intravenous injection of the same amount of IL-6 did not induce SAP gene transcription above constitutive levels in untreated mice.
“However, the IV injection of the same amount of IL-6 did not induce SAP gene transcription above the constitutive levels observed in untreated mice (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data
In agreement with previous work, the authors found high mortality of IL-6-deficient mice after partial hepatectomy.
“In agreement with previous works, we found a high mortality of IL-6 -deficient mice.”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 knockout mice and wild-type controls are comparable except for the IL-6 deficiency, including their genetic background.
- Findingcitation
IL-6-deficient mice display increased susceptibility to perioperative morbidity and mortality after partial hepatectomy.
“IL-6 -deficient mice display an increased susceptibility to perioperative morbidity and mortality after PH (Fig. 1).6”
- Also stated in: § Discussion · plain
“Of 14 wild-type mice (f), 12 survived beyond 7 days, but only 2 of 12 IL-6 -deficient mice (Œ).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Cressman, 1995, Hepatology source
- Also stated in: § Discussion · plain
- Findingown data
In IL-6 KO mice, average liver weight was 5.042% of body weight (95% CI ±0.089; n=6).
“In IL-6 KO mice, the average liver weight was 5.042% of the body weight (95% CI, Ϯ 0.089; n ϭ 6).”
Quote in the paperNot a substantial claim - Findingown data
c-myc is also absent in IL-6 KO mice during the first 8 hours after partial hepatectomy.
“Further evidence for a cyclin D1-independent cell cycle progression in the first round of hepatocyte division comes from analysis of c-myc, which is also absent in the IL-6 KO mice during the first 8 hours after PH (Fig. 5B).”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Premisecitation
IL-6 is a critical inducer of the acute phase response in the liver.
“IL-6 is a critical inducer of the acute phase (AP) response in the liver, 11”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Kopf, 1994, Nature source
- Interpretationown data
The major role of IL-6 is the induction of an adaptive response to partial hepatectomy that ensures body homeostasis and survival.
“We conclude that the major role of IL-6 is the induction of an adaptive response to PH that ensures body homeostasis and survival.”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 knockout mice and wild-type controls are comparable except for the IL-6 deficiency, including their genetic background.
- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Interpretationown data
A sustained action of IL-6 is required to prevent high postoperative mortality in IL-6-deficient mice.
“showing the requirement of a sustained action of IL-6.”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 knockout mice and wild-type controls are comparable except for the IL-6 deficiency, including their genetic background.
- Interpretationreasoning
The main contribution of liver regeneration in IL-6 KO mice comes from liver cell proliferation.
“But overall, as in wildtype mice, the main contribution of liver regeneration in IL-6 KO mice comes from liver cell proliferation.”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Interpretationown data
IL-6 is not required for liver cell proliferation after partial hepatectomy.
“We conclude that IL-6 is not required for liver cell proliferation, but has an essential role in recovery and survival after PH.”
Quote in the paperSubstantial claim- Rests on an assumption: The subset of IL-6 KO mice that survived in good health after partial hepatectomy is representative for assessing whether IL-6 is required for liver cell proliferation.
- Interpretationown data
The formation of the cyclin E-CDK2 complex in the absence of cyclin D1 is most probably through the action of cyclin D3-CDK6.
“most probably through the action of cyclin D3-CDK6”
Quote in the paperNot a substantial claim - Interpretationown data
Liver mass restoration in IL-6 KO mice is not due to liver cell growth without proliferation.
“Liver mass restoration could be a result of liver cell growth without proliferation, but based on our BrdU labeling and cell counting experiments we have to reject this explanation.”
Quote in the paperSubstantial claim - Interpretationown data
Up-regulation of cyclin D1 in the absence of IL-6 is not responsible for cell cycle progression in these IL-6 KO mice.
“Therefore, up-regulation of cyclin D1 in the absence of IL-6 is not responsible for cell cycle progression in our IL-6 KO mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Premisecitation
Hepatocyte proliferation induced by hepatomitogens is not impaired in IL-6 KO mice.
“The first part of this conclusion is supported by the observation that hepatocyte proliferation induced by hepatomitogens is not impaired in IL-6 KO mice.26”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Ledda-Columbano, 1998, Oncogene source
- Interpretationown data
Loss of cyclin D1 induction in IL-6 KO mice does not prevent activation of the cyclin E-CDK2 complex.
“In conclusion, the loss of cyclin D1 induction in IL-6 KO mice does not prevent the activation of the cyclin E-CDK2 complex.”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Interpretationown data
The essential role of IL-6 in liver regeneration is the induction of an acute-phase response in the remaining liver.
“In conclusion, we provide evidence that the essential role of IL-6 in liver regeneration is the induction of an AP response in the remaining liver.”
Quote in the paperSubstantial claim - Interpretationown data
A sustained IL-6 signal is important for survival after partial hepatectomy.
“These data confirm the important role of a sustained IL-6 signal for the survival after PH.”
Quote in the paperSubstantial claim - Interpretationreasoning
Cell cycle regulation in proliferating hepatocytes has a considerable degree of plasticity and variability.
“Our work adds to a growing body of evidence that cell cycle regulation in proliferating hepatocytes has a considerable degree of plasticity and variability.”
Quote in the paperNot a substantial claim - Interpretationown data
Up-regulation of c-myc and cyclin D1 is not required for liver cell proliferation.
“We show here that the up-regulation of c-myc and cyclin D1 is not required for liver cell proliferation.”
Quote in the paperSubstantial claim- Rests on an assumption: The subset of IL-6 KO mice that survived in good health after partial hepatectomy is representative for assessing whether IL-6 is required for liver cell proliferation.
- Interpretationown data
The binding of cyclin D3 and the absence of p27Kip1 could result in a more active CDK6, compensating for the loss of the cyclin D1-CDK4 complex.
“The binding of cyclin D3 and the absence of the inhibitor could result in a more active CKD6, compensating for the loss of the cyclin D1-CDK4 complex.”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
- Premisecitation
In both IL-6 KO and TNFR1 KO mouse models, injection of IL-6 30 minutes before surgery rescued the impaired response to partial hepatectomy.
“In both knockout (KO) mouse models, an injection of IL-6 30 minutes before surgery rescued the impaired response to PH.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Cyclin D1 is nonessential for liver cell proliferation.
“However, cyclin D1 seems to be nonessential for liver cell proliferation.”
- Also stated in: § Discussion · plain
“Cyclin D1deficient mice have normal livers, and recent studies in cyclin D1-deficient mice describe essentially undisturbed hepatocyte proliferation after stimulation with the potent mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene.32”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Ledda-Columbano, 2002, Hepatology source
- Also stated in: § Discussion · plain
- Interpretationown data
The short duration of STAT3 activation after intravenous IL-6 results in insufficient up-regulation of acute phase proteins.
“We conclude that the short duration of STAT3 activation after IV injection of IL-6 results in an insufficient up-regulation of AP proteins.”
Quote in the paperSubstantial claim - Interpretationreasoning
Induction of the cell cycle proteins c-myc and cyclin D1 is not a requirement for liver regeneration.
“The induction of the cell cycle proteins c-myc and cyclin D1 helps to promote liver cell proliferation, but is not a requirement for liver regeneration.”
Quote in the paperNot a substantial claim
- May combine two claims. 19
- Classified as probably not a substantial claim. 9
- The quote only partly states this claim. 1
May combine two claims.
Findingown dataHigh postoperative mortality of IL-6-deficient mice can be completely prevented by subcutaneous IL-6 treatment but not by intravenous IL-6 treatment.
“The high postoperative mortality of IL-6 -deficient mice could be completely prevented by SC, but not by IV IL-6 treatment, showing the requirement of a sustained action of IL-6.”
- Also stated in: § Abstract · plain
“SC, but not IV, IL-6 injections can protect IL-6deficient mice from excess mortality.”
- Also stated in: § Mortality After PH. · plain
“SC IL-6 treatment allowed 86% survival, whereas an IV injection could not rescue the IL-6 KO mice.”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 knockout mice and wild-type controls are comparable except for the IL-6 deficiency, including their genetic background.
- Also stated in: § Abstract · plain
May combine two claims.
Findingown dataIn IL-6 KO mice after partial hepatectomy, subcutaneous IL-6 substitution corrects high mortality, whereas intravenous IL-6 does not.
“We found that the high mortality observed in IL-6 KO mice could be corrected by SC, but not by IV IL-6 substitution.”
- Also stated in: § Discussion · plain
“SC injection of IL-6 resulted in survival of 86% (}), not different from the wild-type mice.The injection of the same amount of IL-6 into the tail vein could not improve survival of IL-6 KO mice (F).”
Quote in the paperSubstantial claim- Also stated in: § Discussion · plain
May combine two claims.
Findingown dataBoth cyclins D2 and D3 are present in liver extracts, but neither is up-regulated during the G1 phase of the cell cycle in IL-6 KO mice.
“As shown in Fig. 5C and 5D, both cyclins are present in liver extracts, but neither of them is up-regulated during the G1 phase of the cell cycle.”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
May combine two claims.
Findingown dataThe cyclin D3-CDK6 complex is free of the inhibitor p27 Kip1 during liver regeneration in IL-6 KO mice, but not in controls.
“a complex we found free of the inhibitor p27 Kip1 during liver regeneration in IL-6 KO mice, but not in controls.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn IL-6 KO mice, cyclin D1 up-regulation remains undetectable in the first 48 hours and is up-regulated only later at 72 and 96 hours.
“In IL-6 KO mice, cyclin D1 up-regulation remains undetectable in the first 48 hours and is up-regulated only later, at 72 hours and 96 hours (Fig. 5A).”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
May combine two claims.
Findingown dataSubcutaneous IL-6 treatment allowed 86% survival in IL-6 KO mice, whereas intravenous injection did not rescue them.
“SC IL-6 treatment allowed 86% survival, whereas an IV injection could not rescue the IL-6 KO mice.”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 knockout mice and wild-type controls are comparable except for the IL-6 deficiency, including their genetic background.
May combine two claims.
Findingown dataIntravenous IL-6 resulted in rapid but transient STAT3 activation that lasted 2 hours and was very weak after 4 hours.
“The IV route resulted in a rapid but transient STAT3 activation that lasted 2 hours and was very weak after 4 hours.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter subcutaneous injection of recombinant human IL-6, peak serum IL-6 concentrations occurred later (30 minutes vs 10 minutes for IV) and elevated concentrations persisted up to 4 hours.
“Indeed, peak concentrations were measured later (after 30 minutes vs. 10 minutes in IV-injected animals), and elevated IL-6 concentrations were found up to 4 hours after SC injections of 500 ng/g body weight rhIL-6 (Fig. 2A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe cells in IL-6 KO livers look slightly larger but otherwise normal, without increased glycogen or fat content.
“The cells look slightly larger in IL-6 KO mice, but are otherwise normal, without increased glycogen or fat content.”
Quote in the paperNot a substantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
May combine two claims.
Findingown dataBinucleated hepatocytes were 4.8% in wild-type and 5.8% in IL-6 KO mice, a difference not significant.
“We found that 4.8% of the hepatocytes were binucleated in wild-type, and 5.8% in IL-6 KO mice, a difference that is not significant in our context.”
Quote in the paperNot a substantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
May combine two claims.
Findingown dataAfter subcutaneous IL-6, STAT3 remained strongly activated for the first 4 hours and was detectable up to 8 hours.
“After SC application, STAT3 remained strongly activated in the first 4 hours and was detectable in electrophoretic mobility shift assays for up to 8 hours (Fig. 2B).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIL-6 is the principal activator of STAT3, whereas TNF-alpha induces NF-kB.
“Interleukin 6 (IL-6) was identified as the principal activator of STAT3, whereas tumor necrosis factor ␣ (TNF-␣) induces NFB.7,8”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSeveral immediate early genes induced after partial hepatectomy are target genes of STAT3 and NF-kB.
“Several of these induced genes are target genes of signal transducer and activator of transcription (STAT)3 and nuclear factor kappa B (NFB), two transcription factors that are activated early during liver regeneration.5,6”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMitogenic signals for hepatocytes are transported in the blood and induce immediate early genes within 30 minutes after partial hepatectomy.
“Convincing evidence has been found that mitogenic signals for hepatocytes are transported in the blood 2,3 and that they induce a number of immediate early genes within 30 minutes after PH. 4”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationIL-6-deficient mice suffer significant morbidity and mortality after partial hepatectomy.
“It was reported previously that IL-6 KO mice suffer from significant morbidity and mortality after PH and that the mice could be protected by SC injection of IL-6 30 minutes before surgery.7”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Cressman, 1996, Science source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThere were no differences in body weight between IL-6 KO animals and controls.
“The size of females was between 19 and 22 g, the size of males between 26 and 30 g, with no differences between KO animals and controls.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenIn all experiments, controls were age- and sex-matched.
“In all experiments, controls were age-and sex-matched.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataIL-6 KO mice have fewer cells per area, but the difference is small and not compatible with a cell growth without division mechanism for restoration of liver mass.
“IL-6 KO mice do have fewer cells per area, but the difference is small and not compatible with a cell growth without division mechanism for restoration of liver mass in IL-6 KO mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
Classified as probably not a substantial claim. The quote only partly states this claim.
Study design and conductown dataFor liver regeneration analysis, only IL-6 KO mice in a good state of health after partial hepatectomy were analyzed.
“For this experiment, only mice in a good state of health after PH were analyzed.”
- Also stated in: § Liver Regeneration in IL-6 -Deficient Mice That Survive After PH. · plain
“The sick mice were spared from further experiments and euthanized and not used for further analysis.”
Quote in the paperSubstantial claim- Also stated in: § Liver Regeneration in IL-6 -Deficient Mice That Survive After PH. · plain
May combine two claims.
Interpretationown dataCell cycle progression in IL-6 KO mice is somewhat slower, but finally takes place with the help of compensatory cyclin D3-CDK6 activation.
“Cell cycle progression in the KO mice is somewhat slower, but finally takes place with the help of compensatory cyclin D3-CDK6 activation.”
Quote in the paperSubstantial claim- Rests on an assumption: The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCyclin D1 is up-regulated during liver regeneration after partial hepatectomy.
“Cyclin D1 is up-regulated during liver regeneration after PH, 7,28,29”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOverexpression of cyclin D1 in hepatocytes promotes hepatocyte proliferation in vitro and in vivo.
“overexpression of cyclin D1 in hepatocytes promotes hepatocyte proliferation in vitro and in vivo.30,31”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [30] Albrecht, 1999, Cell Growth Differ
- cites [31] Nelsen, 2001, Cancer Res
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCyclin E can compensate for loss of cyclin D1.
“Furthermore, not only other D type cyclins, but also cyclin E can compensate for loss of D1. 19”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Bowe, 2002, Oncogene source
May combine two claims.
Interpretationown dataIL-6 has an essential role in recovery and survival after partial hepatectomy.
“We conclude that IL-6 is not required for liver cell proliferation, but has an essential role in recovery and survival after PH.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningCompensatory mechanisms correct for the absence of c-myc and cyclin D1 induction in IL-6 KO mice, because liver cell proliferation takes place.
“it is obvious that compensatory mechanisms correct for the absence of c-myc and cyclin D1 induction, because liver cell proliferation clearly takes place in IL-6 KO mice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationnone givenInduction of the cell cycle proteins c-myc and cyclin D1 helps to promote liver cell proliferation.
“The induction of the cell cycle proteins c-myc and cyclin D1 helps to promote liver cell proliferation, but is not a requirement for liver regeneration.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
IL-6 knockout mice and wild-type controls are comparable except for the IL-6 deficiency, including their genetic background.
“Eight-to 12-week old IL-6 -deficient mice (Jackson Laboratories, Bar Harbor, Maine; strain name B6; 129S2-Il6tm1Kopf; original reference 11) and C57Bl/6J mice (Biological Research Laboratories, Fu ¨llinsdorf, Switzerland) were used for the PH experiments.”
“In all experiments, controls were age-and sex-matched.”
The paper relies on this without support.
The IL-6 knockout mice that survive partial hepatectomy in good health are representative of all IL-6 knockout mice that survive partial hepatectomy.
“For this experiment, only mice in a good state of health after PH were analyzed.”
“The sick mice were spared from further experiments and euthanized and not used for further analysis.”
The paper relies on this without support.
The subset of IL-6 KO mice that survived in good health after partial hepatectomy is representative for assessing whether IL-6 is required for liver cell proliferation.
“We then focused on the analysis of liver regeneration in the subset of IL-6 KO mice that survived well and in apparently good health after PH.”
“The different results of the BrdU labeling experiments in our work compared with the previous report 7 could result from our exclusion of all sick mice for the analysis of liver regeneration after PH, or from the use of different mouse strains.”
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?
Deletion of il6 in mice impairs compensatory hepatocyte proliferation by reducing STAT3 activation, promoting liver failure, which can be corrected by IL-6 treatment.
“The IL-6-promoted liver regeneration was determined in IL-6 knockout mice, as the deletion of il6 impaired the compensatory proliferation of hepatocytes by reducing the downstream STAT3 activation [3, 4], thus promoting liver failure, which could be corrected by the treatment of IL-6.”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [3]
The Discussion says that surviving IL-6 knockout mice restored liver mass without a significant growth difference and concludes that IL-6 is not required for liver cell proliferation—contrary to the claimed impairment of compensatory proliferation. The paper does report increased mortality after partial hepatectomy and rescue with subcutaneous IL-6, but attributes the survival benefit to a sustained acute-phase response, not to correction of a STAT3-mediated proliferation defect. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredDeletion of the il6 gene impairs hepatocyte homeostasis and liver regeneration.
“However, the deletion of il6 gene also impairs the hepatocyte homeostasis and liver regeneration [3–5].”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [3]
The Discussion (page unavailable) reports that IL-6-deficient mice had much poorer survival after partial hepatectomy, supporting a role for IL-6 in recovery. But the Liver Regeneration section (page unavailable) says surviving knockout mice restored liver mass as well as controls, and the paper does not establish impaired baseline hepatocyte homeostasis. The unqualified claim that deletion impairs liver regeneration therefore overstates the findings. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBoth PAMPs and LPS activate Kupffer cells, which subsequently synthesize IL-6 and TNF-alpha.
“Both PAMPs and LPS activate Kupffer cells, which subsequently synthesize two key cytokines—IL-6[45] and tumour necrosis factor-alpha (TNF-α)[46].”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [45]
The introductory passage and Discussion describe IL-6 and TNF-α in liver regeneration after partial hepatectomy, but neither says that PAMPs or LPS activate Kupffer cells to synthesize IL-6. Searches for Kupffer cells, lipopolysaccharide, and pathogen-associated molecular patterns found no passage establishing that pathway. The separate citation attached to TNF-α is not assessed here. (LLM, conf=0.76)
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.
Hepatocyte counting uses a different number of fields
MinorThe methods say three fields were counted per mouse, but the results say two to three fields were counted per mouse.
“Three high-power microscope fields of 0.31 mm 2 each were counted per mouse and time point.”
“in 8 control mice and 5 IL-6 KO mice (2 to 3 fields for each mouse) 96 hours after PH.”
Figure 5D identifies different CDK partners
MinorThe Figure 5D heading names CDK4, whereas its description says the extracts were immunoprecipitated with CDK6 antibodies.
“(D) Association of cyclin D3 with CDK4 and p27 Kip1 .”
“Extracts were immunoprecipitated with either CDK6 antibodies or with p27 antibodies, followed by Western blots with cyclin D3 specific antibodies.”
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ResultIncreased Hepatic and Circulating Interleukin-6 Levels in Human Nonalcoholic Steatohepatitis
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Non-alcoholic fatty liver disease pathogenesis: The present and the future
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BackgroundRegulation of liver regeneration by growth factors and cytokines
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BackgroundCytokines, STATs and liver disease.
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“Previous concepts suggested that, in the liver, IL-6 has mainly a prosurvival and antiapoptotic action”
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Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-γ)
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“[64]; however, several follow-up studies using IL-6 knockout mice generate conflicting data on the role of IL-6 on hepatocyte proliferation and liver regeneration [65–68].”
BackgroundRegulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3
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New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology
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“However, increasing evidence suggests that IL-6 plays more important role in protection against liver injury, and only a minor role in liver regeneration.(5,6) Several transcription factors are activated shortly after PH or toxic liver injury, including NF-kB, signal transducer and activator of transcription 3 (STAT3)…”
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“In rodents, IL-6 is a progrowth factor required for hepatic regeneration and survival after partial hepatectomy [23, 24].”
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BackgroundHypoxia-Induced Endothelial Proliferation Requires Both mTORC1 and mTORC2
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“A, Western blots showing total cell lysates of serum-deprived RAECs exposed to increasing duration of hypoxia (10 minutes to 24 hours) and probed for (numbering from top to bottom) (1) phosphorylated S6K-Thr389, (2) phosphorylated S6K-Thr389 in the presence of 20 nmol/L rapamycin, (3) total S6K, (4) phosphorylated Akt…”
BackgroundIL‐6 Trans‐signaling Controls Liver Regeneration After Partial Hepatectomy
Fazel Modares, N., Polz, R., Haghighi, F., Lamertz, L., Behnke, K., Zhuang, Y., Kordes, C., Häussinger, D., Sorg, U. R., Pfeffer, K., et al. (2019) · Hepatology · doi:10.1002/hep.30774 · Cited by 113 · see citing works
“Synergistic action of hepatocyte growth factor (HGF) and interleukin 6 (IL-6) controls the early regenerative phase after partial hepatectomy (PHX) by promoting both mitosis and survival of hepatocytes.(1-5) IL-6 binds to the IL-6 receptor (IL-6R), followed by dimerization of glycoprotein 130 (gp130), leading to JAK/S…”
BackgroundInfluentialConcerted Functions of Gab1 and Shp2 in Liver Regeneration and Hepatoprotection
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“from stress and infectious injury (5, 22, 47, 48, 56).”
BackgroundCytokines and STATs in Liver Fibrosis
Kong, X., Horiguchi, N., Mori, M., & Gao, B. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00069 · Cited by 113 · see citing works
“However, numerous studies demonstrated the hepatoprotective role of IL-6 against liver injury in spite of its pro-inflammatory effect (Blindenbacher et al., 2003; Wuestefeld et al., 2003).”
BackgroundArgast, G. M., Campbell, J. S., Brooling, J. T., & Fausto, N. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405703200 · Cited by 104 · see citing works
Characterisation of a Novel Fc Conjugate of Macrophage Colony-stimulating Factor
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“These data are consistent with the recent demonstration of high IL-18 levels in the liver of patients with fulminant hepatic failure 30 42 and suggest that overexpression of IL-18 may cause substantial liver injury in vivo.”
Advances in Alcoholic Liver Disease
Beier, J. I., Arteel, G. E., & McClain, C. J. (2010) · Current Gastroenterology Reports · doi:10.1007/s11894-010-0157-5 · Cited by 97 · see citing works
“IL-6 is also involved in induction of an acute-phase response in the remaining liver tissue [ 44 ].”
BackgroundMarkers of liver regeneration—the role of growth factors and cytokines: a systematic review
Hoffmann, K., Nagel, A. J., Tanabe, K., Fuchs, J., Dehlke, K., Ghamarnejad, O., Lemekhova, A., & Mehrabi, A. (2020) · BMC Surgery · doi:10.1186/s12893-019-0664-8 · Cited by 94 · see citing works
IL-22 is involved in liver regeneration after hepatectomy
Ren, X., Hu, B., & Colletti, L. M. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00075.2009 · Cited by 109 · see citing works
“It is well documented that mice deficient in IL-6 regenerate their livers more slowly than normal animals after a variety of injuries and that stat-3 binding is also decreased in these animals (3, 19).”
BackgroundT cell-derived lymphotoxin regulates liver regeneration
Tumanov, A. V., Koroleva, E. P., Christiansen, P. A., Khan, M. A., Ruddy, M. J., Burnette, B., Papa, S., Franzoso, G., Nedospasov, S. A., Fu, Y., et al. (2009) · Gastroenterology · doi:10.1053/j.gastro.2008.09.015 · Cited by 89 · see citing works
Marshall, K. M., He, S., Zhong, Z., Atkinson, C., & Tomlinson, S. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20131902 · Cited by 85 · see citing works
“IL-6 expression is dependent on TNF-induced NF-B activation, and IL-6–induced activation of STAT3 plays a role in cell cycle progression (Cressman et al., 1996; Yamada et al., 1997; Li et al., 2002; Blindenbacher et al., 2003).”
BackgroundMarkiewski, M. M., DeAngelis, R. A., & Lambris, J. D. (2005) · Molecular Immunology · doi:10.1016/j.molimm.2005.06.019 · Cited by 86 · see citing works
“Some recent studies have emphasized the hepatop ive role of IL-6 more strongly than its mitogenic activ Blindenbacher et al., 2003; Sakamoto et al., 1999; Wu eld et al., 2003).”
BackgroundThe double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases
Wang, M.-J., Zhang, H.-L., Chen, F., Guo, X.-J., Liu, Q.-G., & Hou, J. (2024) · Experimental Hematology & Oncology · doi:10.1186/s40164-024-00527-1 · Cited by 84 · see citing works
Impact of interleukin-6 classic- and trans-signaling on liver damage and regeneration
Drucker, C., Gewiese, J., Malchow, S., Scheller, J., & Rose-John, S. (2010) · Journal of Autoimmunity · doi:10.1016/j.jaut.2009.08.003 · Cited by 83 · see citing works
Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses
Liu, Y., Shao, M., Wu, Y., Cheng, Y., Jiang, S., Liu, J., Dai, J., Liu, Y., Li, J. X., Jia, W., et al. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.10.022 · Cited by 84 · see citing works
“For instance, animal model studies have established the importance of interleukin 6 (IL-6) in stimulating liver regeneration after partial hepatectomy (PH) or during hepatotoxin carbon tetrachloride (CCl4)-induced injury [7–10].”
BackgroundTeoh, N., Field, J., & Farrell, G. C. (2006) · Journal of Hepatology · doi:10.1016/j.jhep.2006.01.039 · Cited by 78 · see citing works
da Silva, C. G., Studer, P., Skroch, M., Mahiou, J., Minussi, D. C., Peterson, C. R., Wilson, S. W., Patel, V. I., Ma, A., Csizmadia, E., et al. (2013) · Hepatology · doi:10.1002/hep.26197 · Cited by 77 · see citing works
Advances in the regulation of liver regeneration
Jia, C. (2011) · Expert Review of Gastroenterology & Hepatology · doi:10.1586/egh.10.87 · Cited by 75 · see citing works
Lee, J. K., Bettencourt, R., Brenner, D. A., Le, T., Barrett-Connor, E. L., & Loomba, R. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034218 · Cited by 74 · see citing works
“In rodents, IL-6 is a pro-growth factor required for hepatic regeneration and survival after partial hepatectomy [25,26].”
BackgroundNaseem, S., Hussain, T., & Manzoor, S. (2018) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2018.01.002 · Cited by 72 · see citing works
IL-6 modulates hepatocyte proliferation via induction of HGF/p21cip1: Regulation by SOCS3
Sun, R., Jaruga, B., Kulkarni, S., Sun, H., & Gao, B. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.10.171 · Cited by 72 · see citing works
Przybyt, E., Krenning, G., Brinker, M. G. L., & Harmsen, M. C. (2013) · Journal of Translational Medicine · doi:10.1186/1479-5876-11-39 · Cited by 69 · see citing works
“Furthermore, IL-6 facilitates healing of damaged skeletal muscle through mitotic stimulation of muscle progenitor cells [20,21].”
BackgroundHoriguchi, N., Lafdil, F., Miller, A. M., Park, O., Wang, H., Rajesh, M., Mukhopadhyay, P., Fu, X. Y., Pacher, P., & Gao, B. (2010) · Hepatology · doi:10.1002/hep.23532 · Cited by 65 · see citing works
“produced, interleukin-6 (IL-6) has been shown to be a hepatoprotective cytokine in this model(15) as well as in several other liver injury models, including ischemia/ reperfusion, partial hepatectomy, alcoholic and nonalcoholic fatty liver, and concanavalin A (Con A)– induced T cell hepatitis.(16-20) Additionally, the…”
BackgroundJAK-STAT signaling in hepatic fibrosis
Mair, M. (2011) · Frontiers in bioscience · doi:10.2741/3886 · Cited by 63 · see citing works
“IL-6-deficient mice are more susceptible to liver injury induced by ethanol (60), Con A (46, 61) acetaminophen (62, 63) and bile acids (64), suggesting that IL-6 has protective functions (65, 66).”
BackgroundRole of biomaterials, therapeutic molecules and cells for hepatic tissue engineering
Vasanthan, K. S., Subramanian, A., Krishnan, U. M., & Sethuraman, S. (2012) · Biotechnology Advances · doi:10.1016/j.biotechadv.2012.01.004 · Cited by 64 · see citing works
Echevarria, F. D., Formichella, C., & Sappington, R. M. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00318 · Cited by 53 · see citing works
“Scale bars= 100µm for all images. strongly associated with wound healing and tissue regeneration in other systems (Blindenbacher et al., 2003; Lin et al., 2003; Tiberio et al., 2008; McFarland-Mancini et al., 2010).”
BackgroundPlacenta extract promote liver regeneration in CCl4-injured liver rat model
Jung, J., Lee, H., Lee, J. M., Na, K.-H., Hwang, S. G., & Kim, G. J. (2011) · International Immunopharmacology · doi:10.1016/j.intimp.2011.02.012 · Cited by 61 · see citing works
Longo, C. R., Patel, V. I., Shrikhande, G. V., Scali, S. T., Csizmadia, E., Daniel, S., Sun, D. W., Grey, S. T., Arvelo, M. B., & Ferran, C. (2005) · Hepatology · doi:10.1002/hep.20741 · Cited by 60 · see citing works
Annexin Animal Models—From Fundamental Principles to Translational Research
Grewal, T., Rentero, C., Enrich, C., Wahba, M., Raabe, C. A., & Rescher, U. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073439 · Cited by 58 · see citing works
Cheng, L., Wang, J., Li, X., Xing, Q. R., Du, P., Su, L., & Wang, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017631 · Cited by 55 · see citing works
“IL-6 could promote liver regeneration [19–21] and protects hepatocyte death induced by concanavalin A (ConA), anti-Fas, alcohol, acetaminophen, or carbon tetrachloride mediated hepatic damage through the signal transducer and activator of transcription 3 (STAT3) pathway after engaging the heterodi-”
BackgroundSerum Levels of Interleukin-6 and Its Soluble Receptors in Patients with Hepatitis C Virus Infection
Migita, K., Abiru, S., Maeda, Y., Daikoku, M., Ohata, K., Nakamura, M., Komori, A., Yano, K., Yatsuhashi, H., Eguchi, K., et al. (2006) · Human Immunology · doi:10.1016/j.humimm.2006.02.025 · Cited by 51 · see citing works
Molecular dissection of gp130-dependent pathways in hepatocytes during liver regeneration
Dierssen, U., Beraza, N., Lutz, H. H., Liedtke, C., Ernst, M., Wasmuth, H. E., & Trautwein, C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m705483200 · Cited by 48 · see citing works
Amemiya, H., Kono, H., & Fujii, H. (2009) · Journal of Surgical Research · doi:10.1016/j.jss.2009.08.008 · Cited by 47 · see citing works
“Tumor necrosis factor (TNF)-a and interleukin (IL)-6 have been implicated as important factors for initiating the regenerative responses after PH, a conclusion derived from studies with anti-TNF-a antibodies and mice lacking TNFR-1 or IL-6 [1, 2].”
BackgroundAhmed, Y. A., Fu, Y., Rodrigues, R. M., He, Y., Guan, Y., Guillot, A., Ren, R., Feng, D., Hidalgo, J., Ju, C., et al. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00731-7 · Cited by 46 · see citing works
IL-6 Promotes compensatory liver regeneration in cirrhotic rat after partial hepatectomy
Tiberio, G. A. M., Tiberio, L., Benetti, A., Cervi, E., Montani, N., Dréano, M., Garotta, G., Cerea, K., Steimberg, N., Pandolfo, G. P., et al. (2008) · Cytokine · doi:10.1016/j.cyto.2008.03.012 · Cited by 45 · see citing works
“Among several cytokines and growth factors involved in liver regeneration, IL-6 has been shown to play a major role [3,4].”
BackgroundRad50 Is Dispensable for the Maintenance and Viability of Postmitotic Tissues
Adelman, C. A., De, S., & Petrini, J. H. J. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01525-08 · Cited by 45 · see citing works
Vaquero, J., Campbell, J. S., Haque, J. A., McMahon, R. S., Riehle, K. J., Bauer, R. L., & Fausto, N. (2011) · Hepatology · doi:10.1002/hep.24420 · Cited by 45 · see citing works
“KO – – 52 (10-133) – 51 (40-59) 1 (0-10) 83 (73-85)”
MicroRNAs in Liver Regeneration
Chen, X., Zhao, Y., Wang, F., Bei, Y., Xiao, J., & Yang, C. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000430381 · Cited by 44 · see citing works
Tachibana, S., Zhang, X., Ito, K., Ota, Y., Cameron, A. M., Williams, G. M., & Sun, Z. (2014) · Cell & Bioscience · doi:10.1186/2045-3701-4-6 · Cited by 43 · see citing works
“While IL-6 has been shown to be vital for liver regeneration [6,13,14], the specific mechanisms and factors involved remain incompletely defined.”
BackgroundA Critical Role for Matrix Metalloproteinases in Liver Regeneration
Alwayn, I. P. J., Verbesey, J. E., Kim, S., Roy, R., Arsenault, D. A., Greene, A. K., Novak, K., Laforme, A., Lee, S., Moses, M. A., et al. (2008) · Journal of Surgical Research · doi:10.1016/j.jss.2007.04.002 · Cited by 43 · see citing works
“tion factor that initiates hepatocyte replication [7].”
Canna, S., Frankovich, J., Higgins, G. C., Narkewicz, M. R., Nash, S., Hollister, J. R., Soep, J. B., & Dragone, L. L. (2009) · Pediatric Rheumatology · doi:10.1186/1546-0096-7-21 · Cited by 43 · see citing works
“In contrast, signaling through TNFα and IL-6 receptors on hepatocytes can elicit signals that promote liver regeneration [17,18].”
BackgroundNechemia-Arbely, Y., Shriki, A., Denz, U., Drucker, C., Scheller, J., Raub, J., Pappo, O., Rose-John, S., Galun, E., & Axelrod, J. H. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2010.08.017 · Cited by 42 · see citing works
“IL-6 expression, which dramatically increases shortly following PH [4], appears to be critical to the early onset of liver regeneration and has been shown to mediate both pro-mitotic and pro-survival activities within the regenerative process [5–8], although, the specific role of IL-6 in the mitotic response remains c…”
BackgroundWang, H., Park, O., Lafdil, F., Shen, K., Horiguchi, N., Yin, S., Fu, X.-Y., Kunos, G., & Gao, B. (2009) · Hepatology · doi:10.1002/hep.23430 · Cited by 41 · see citing works
Álvarez-Guaita, A., Blanco‐Muñoz, P., Meneses‐Salas, E., Wahba, M., Pollock, A. H., Jose, J., Casado, M., Bosch, M., Artuch, R., Gaus, K., et al. (2020) · Hepatology · doi:10.1002/hep.31232 · Cited by 41 · see citing works
“(2) Intriguinly, whereas the majority of knockout mouse models described to date display a delayed, rather than complete, abrogation of regeneration,(1) the present study identifies AnxA6 as a decisive factor crucial in the posthepatectomy phase, a feature that is documented only for a rare number of genes.(23,28,29)…”
BackgroundLiver regeneration--the best kept secret. A model of tissue injury response.
Cienfuegos, J. A., Rotellar, F., Baixauli, J., Martínez-Regueira, F., Pardo, F., & Hernández-Lizoáin, J. L. (2014) · PubMed · Cited by 40 · see citing works
Mechanisms of interleukin-6 protection against ischemia–reperfusion injury in rat liver
Tiberio, L., Tiberio, G. A. M., Bardella, L., Cervi, E., Cerea, K., Dréano, M., Garotta, G., Fra, A., Montani, N., Bravo, A. F., et al. (2006) · Cytokine · doi:10.1016/j.cyto.2006.04.009 · Cited by 40 · see citing works
Shteyer, E., Yaʼacov, A. B., Zolotaryova, L., Sinai, A., Lichtenstein, Y., Pappo, O., Kryukov, O., Elkayam, T., Cohen, S., & Ilan, Y. (2014) · Acta Biomaterialia · doi:10.1016/j.actbio.2014.02.047 · Cited by 39 · see citing works
Muriel, P. (2007) · Wiley eBooks · doi:10.1002/9780470516751.ch14 · Cited by 39 · see citing works
Schisandrol B promotes liver regeneration after partial hepatectomy in mice
Li, X., Sun, J., Fan, X., Guan, L., Li, D., Zhou, Y., Zeng, X., Chen, Y., Zhang, H., Xu, L., et al. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.10.044 · Cited by 36 · see citing works
Protective Effects of Early CD4+ T Cell Reduction in Hepatic Ischemia/Reperfusion Injury
Martin, M., Mory, C., Prescher, A., Wittekind, C., Fiedler, M., & Uhlmann, D. (2009) · Journal of Gastrointestinal Surgery · doi:10.1007/s11605-009-1104-3 · Cited by 36 · see citing works
Interleukin-18: a pro-inflammatory cytokine that plays an important role in acute pancreatitis
Yuan, B., Zhu, R.-M., Braddock, M., et al. (2007) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.11.10.1261 · Cited by 35 · see citing works
“More studies demonstrated that high IL-18 levels in the liver of patients with fulminant hepatic failure [81,82] and overexpression of IL-18 may cause substantial liver injury in vivo [72] .”
BackgroundResolving the Role of Il–6 in Liver Regeneration
Zimmers, T. A., Pierce, R. H., McKillop, I. H., & Koniaris, L. G. (2003) · Hepatology · doi:10.1016/j.hep.2003.09.021 · Cited by 35 · see citing works
Chae, M. S., Moon, K. U., Chung, H. S., Park, C. S., Lee, J., Choi, J. H., & Hong, S. H. (2018) · PLoS ONE · doi:10.1371/journal.pone.0195262 · Cited by 34 · see citing works
Graf, D., Kohlmann, C., Haselow, K., Gehrmann, T., Bode, J. G., & Häussinger, D. (2006) · Hepatology · doi:10.1002/hep.21368 · Cited by 32 · see citing works
Nakamura, T., Ueno, T., Sakamoto, M., Sakata, R., Torimura, T., Hashimoto, O., Ueno, H., & Sata, M. (2004) · Journal of Hepatology · doi:10.1016/j.jhep.2004.08.015 · Cited by 33 · see citing works
“This effect seems to be in agreement with previous results reported by other investigators; IL-6 has been described as an acute-phase inducer in the liver and its induction time is several hours after a variety of liver-injury, such as toxic damage, partial hepatectomy, and ischemic liver injury [5,56–58].”
BackgroundResultJin, C., Samuelson, L., Cui, C.-B., et al. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.05.094 · Cited by 32 · see citing works
“Previous studies showed multiple signaling pathways, including EGF [4,19], IL-6 [20,21] and Wnt [22–24], have vital roles in liver regeneration and oval cell activation after liver injury.”
BackgroundRen, X., Hu, B., & Colletti, L. M. (2008) · Surgery · doi:10.1016/j.surg.2008.03.021 · Cited by 31 · see citing works
Gomez, D. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i5.657 · Cited by 31 · see citing works
Uhlmann, D., Gaebel, G., Armann, B., Ludwig, S., Hess, J., Pietsch, U., Fiedler, M., Tannapfel, A., Hauss, J., & Witzigmann, H. (2005) · Surgery · doi:10.1016/j.surg.2005.07.006 · Cited by 31 · see citing works
Regulation of mammalian cell cycle progression in the regenerating liver
Chauhan, A., Lorenzen, S., Herzel, H., & Bernard, S. (2011) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2011.05.026 · Cited by 30 · see citing works
“Our aim is to address one cycle of division during liver regeneration triggered by a decaying damage (Hayashi et al., 2003; Blindenbacher et al., 2003).”
BackgroundZeini, M., Hortelano, S., Través, P. G., Gómez-Valadés, A. G., Pujol, A., Perales, J. C., Bartrons, R., & Boscá, L. (2005) · The FASEB Journal · doi:10.1096/fj.04-3233fje · Cited by 30 · see citing works
“factors, such as NF-κB (10) and Stat-3 (11), although their exact contribution has been subject of debate (8, 12).”
BackgroundHuard, J., Mueller, S., Gilles, E. D., Klingmüller, U., & Klamt, S. (2012) · The FEBS Journal · doi:10.1111/j.1742-4658.2012.08572.x · Cited by 29 · see citing works
Genomic dissection of the cytokine-controlled STAT5 signaling network in liver
Hosui, A., & Hennighausen, L. G. (2008) · Physiological Genomics · doi:10.1152/physiolgenomics.00048.2008 · Cited by 29 · see citing works
Anatomy, pathophysiology and basic mechanisms of disease
Crawford, J. M., & Burt, A. D. (2011) · Elsevier eBooks · doi:10.1016/b978-0-7020-3398-8.00001-5 · Cited by 29 · see citing works
Reusswig, F., Fazel Modares, N., Brechtenkamp, M., Wienands, L., Krüger, I., Behnke, K., Lee‐Sundlov, M. M., Herebian, D., Scheller, J., Hoffmeister, K. M., et al. (2021) · Hepatology · doi:10.1002/hep.31698 · Cited by 28 · see citing works
“IL- 6 is critically involved in hepatocyte proliferation and liver regeneration after PHx.(44,45) To investigate whether IL- 6 is able to stimulate thrombopoiesis, we treated mice with recombinant hIL6.”
Gock, M. C., Eipel, C., Linnebacher, M., et al. (2011) · Microvascular Research · doi:10.1016/j.mvr.2011.03.005 · Cited by 28 · see citing works
Blanc, V., Sessa, K. J., Kennedy, S., Luo, J., & Davidson, N. O. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.115147 · Cited by 28 · see citing works
Lanton, T., Shriki, A., Nechemia‐Arbely, Y., Abramovitch, R., Levkovitch‐Siany, O., Adar, R., Rosenberg, N., Paldor, M., Goldenberg, D., Sonnenblick, A., et al. (2016) · Hepatology · doi:10.1002/hep.29004 · Cited by 28 · see citing works
“0054 by Fisher’s exact test), perhaps reflecting the sensitivity of IL6 knockout mice to liver resection.((18,21,22)) In contrast, we found that a single administration of an antiIL6 mAb (100 lg, intravenously) to Mdr2 (FVB/ NJ) mice, the strain used in our previous study,((16)) at the time of resection did not dimini…”
BackgroundStructure, Function, and Responses to Injury
Crawford, J. M., Bioulac‐Sage, P., & Hytiroglou, P. (2017) · Elsevier eBooks · doi:10.1016/b978-0-7020-6697-9.00001-7 · Cited by 27 · see citing works
Liver Regeneration: A Link to Inflammation through Complement
DeAngelis, R. A., Markiewski, M. M., & Lambris, J. D. (2007) · Springer eBooks · doi:10.1007/0-387-34134-x_2 · Cited by 26 · see citing works
Toll-like receptor 5-mediated signaling enhances liver regeneration in mice
Zhang, W., Wang, L., Sun, X., Liu, X., Xiao, Y., Zhang, J., Wang, T., Chen, H., Zhan, Y., Yu, M., et al. (2021) · Military Medical Research · doi:10.1186/s40779-021-00309-4 · Cited by 25 · see citing works
“Upon the stimulation of these proin ammatory cytokines, normally quiescent hepatocytes regain proliferative competence and become responsive to hepatic growth factors [4,5,6].”
BackgroundBoubaddi, M., Marichez, A., Adam, J., Lapuyade, B., Debordeaux, F., Tlili, G., Chiche, L., & Laurent, C. (2024) · Annals of Surgical Oncology · doi:10.1245/s10434-024-16108-9 · Cited by 25 · see citing works
“24 28 This induction phase ceases as hepatocytes enter the cell cycle (Fig.”
Pathophysiological Changes During Ischemia-reperfusion Injury in Rodent Hepatic Steatosis
Neri, A.-A., Dontas, I. A., Iliopoulos, D., & Karatzas, T. (2020) · In Vivo · doi:10.21873/invivo.11863 · Cited by 24 · see citing works
Wong, S., Ting, Y., Yong, Y.-K., Tan, H.-Y., Barathan, M., Riazalhosseini, B., Bee, C. J., Tee, K. K., Larsson, M., Velu, V., et al. (2021) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365513.2021.1876245 · Cited by 28 · see citing works
Kono, H., Fujii, H., Suzuki‐Inoue, K., Inoue, O., Furuya, S., Hirayama, K., Akazawa, Y., Nakata, Y., Sun, C., Tsukiji, N., et al. (2017) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.13672 · Cited by 24 · see citing works
“Activation of intracellular signaling cascades after hepatectomy The proliferation of hepatocytes requires two sequential phases: a priming phase and progression phase [2,4,5].”
BackgroundInfluential
- Authors
- Blindenbacher, A., Wang, X., Langer, I., Savino, R., Terracciano, L., & Heim, M. H.
- Affiliations
- University Hospital of Basel (CH)
- Magna Graecia University (IT)
- Corresponding author
- Heim, Markus H.
- Venue
- Hepatology
- Published
- 2003-09
- Volume
- 38
- Issue
- 3
- Pages
- 674-682
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2048242463
- Semantic Scholar
- 78c7f4e4325ae9116023347a3571832ba7e4a329
- Cited by
- 202
- References
- 33
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 9 · 2020: 11 · 2019: 6 · 2018: 6 · 2017: 13 · 2016: 5 · 2015: 7 · 2014: 11 · 2013: 5 · 2012: 12
- FWCI
- 6.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- interleukin-6, partial hepatectomy, postoperative survival, acute phase response, liver regeneration, IL-6 knockout mice, homeostasis
- MeSH terms
- Acute-Phase Proteins, Animals, Cell Cycle, DNA-Binding Proteins, Hepatectomy, Injections, Subcutaneous, Liver, Liver Regeneration, Time Factors, Trans-Activators, Interleukin-6, Survival Rate, Mice, Knockout, STAT3 Transcription Factor, Mice
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