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Cited by 156Cytokine Signaling Pathways and InteractionsLiver physiology and pathologyProtein Tyrosine Phosphatases

Expression of suppressors of cytokine signaling during liver regeneration

Open access
Campbell, Jean S., Prichard, Lisa, Schaper, Fred, Schmitz, Jochen, Stephenson-Famy, Alyssa, Rosenfeld, Maryland E., Argast, Gretchen M., Heinrich, Peter C. +1 more·2001·Journal of Clinical Investigation
DOI 10.1172/jci11867PMC PMC209297
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Abstract

The cytokines TNF and IL-6 play a critical role early in liver regeneration following partial hepatectomy (PH). Since IL-6 activates signal transducers and activators of transcription (STATs), we examined whether the suppressors of cytokine signaling (SOCS) may be involved in terminating IL-6 signaling. We show here that SOCS-3 mRNA is induced 40-fold 2 hours after surgery. SOCS-2 and CIS mRNA are only weakly induced, and SOCS-1 is not detectable. SOCS-3 induction after PH is transient and correlates with a decrease in STAT-3 DNA binding and a loss of tyrosine 705 phosphorylation. This response is markedly reduced in IL-6 knockout (KO) mice. TNF injection induces SOCS-3 mRNA in wild-type mice (albeit weakly compared with the increase observed after PH) but not in TNF receptor 1 or IL-6 KO mice. In contrast, IL-6 injection induces SOCS-3 in these animals, demonstrating a requirement for IL-6 in SOCS-3 induction. IL-6 injection into wild-type mice also induces SOCS-1, -2, and CIS mRNA, in addition to SOCS-3. Together, these results suggest that SOCS-3 may be a key component in downregulating STAT-3 signaling after PH and that SOCS-3 mRNA levels in the regenerating liver are regulated by IL-6.

AI snapshot

Written from the paper’s full text.

TL;DR

After partial hepatectomy, SOCS-3 mRNA and protein are induced transiently in mouse liver, correlating with STAT-3 activation and inactivation. IL-6 is a major regulator of this SOCS-3 induction, while TNF alone induces a weaker, different SOCS profile.

Key findings

  • PH induces SOCS-3 mRNA 40- to 50-fold at 2 hours, sustained for 4 hours, declining by 8 hours and returning to baseline by 24 hours; SOCS-3 protein is detected from 2 hours through 8–10 hours. SOCS-2 and CIS are only weakly induced (four- to tenfold, sometimes undetectable), and SOCS-1 is not induced.
  • STAT-3 tyrosine 705 phosphorylation and DNA binding are transient after PH: phosphorylation is first detected at 2 hours and decreases to background by 8 hours; robust DNA binding appears at 2 hours and disappears between 3 and 6 hours. Sham-operated mice show weaker STAT-3 DNA binding.
  • In IL-6 KO mice after PH, SOCS-3 mRNA induction is severely reduced and SOCS-3 protein is not detected; STAT-3 tyrosine phosphorylation is weaker and DNA binding is impaired. Densitometry showed approximately a threefold induction of SOCS-3 at 2 hours in WT versus IL-6 KO liver.
  • TNF injection induces SOCS-3 in WT mice (<15-fold) but not in TNF-R1 or IL-6 KO mice; IL-6 injection induces SOCS-3 40- to 60-fold in all three strains and also induces SOCS-1, -2, and CIS, unlike PH.

Methods

  • Male C57BL/6 WT, IL-6 KO, and TNF-R1 KO mice underwent two-thirds partial hepatectomy or sham laparotomy; some mice received intraperitoneal mTNF (25 µg/kg) or hIL-6 (1 mg/kg), with saline controls.
  • Liver tissue was analyzed by Northern blot for SOCS-1, -2, -3, and CIS mRNA normalized to cyclophilin, by EMSA for STAT DNA binding and supershift, and by immunoprecipitation/immunoblot for STAT-3 phosphorylation and SOCS-3 protein.
  • Data were analyzed by one-way ANOVA followed by Newman-Keuls test; cell culture controls included IL-6-stimulated AML12, HepG2, and RAW 264.7 cells.

Limitations

  • The paper states that more precise analysis of SOCS-3’s role awaits SOCS-3-transgenic or knockout mice, and that such systems require conditional expression because constitutive expression or ablation causes embryonic death.
  • The paper reports that Western blot detection of CIS, SOCS-1, and SOCS-2 proteins was unsuccessful because commercially available antibodies could not detect these proteins in liver lysates.
  • Evident from the text: the main findings are correlative timing and loss-of-function cytokine/receptor models rather than direct SOCS-3 perturbation; the authors also note that a single IL-6 injection does not faithfully reproduce PH signaling and that other cytokines may contribute to SOCS-3 induction after PH.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1172/jci11867

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

9 of 40 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    IL-6 participates in hepatocyte proliferation in vivo not only in PH but in injury-induced models of liver proliferation.

    “These studies and others suggest that IL-6 participates in hepatocyte proliferation in vivo not only in PH but in injury-induced models of liver proliferation (12).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Streetz, 2000, Gut source
  • Findingown data

    No STAT-1 homodimer activity was seen in these experiments.

    “No STAT-1 homodimer activity was seen in these experiments.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Sham-operated mice have a detectable, but much weaker STAT-3 DNA-binding activity.

    “Sham-operated mice have a detectable, but much weaker STAT-3 DNA-binding activity (Figure 1b).”
    Quote in the paperNot a substantial claim
  • Findingown data

    STAT-3 is the major STAT family member activated after PH.

    “Use of STAT-1 and STAT-5 oligonucleotide probes demonstrates that STAT-3 is the major STAT family member activated after PH (Figure 1c).”
    Quote in the paperSubstantial claim
  • Findingown data

    Tyrosine 705 phosphorylation of STAT-3 correlates with its ability to bind DNA.

    “Importantly, tyrosine 705 phosphorylation of STAT-3 correlates with its ability to bind DNA (Figure 1b).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 13
  • May combine two claims. 33

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the liver, IL-6 activates multiple signaling pathways that culminate in the induction of genes involved in growth, hepatocyte-specific metabolic functions, and the acute-phase response.

    “In the liver, IL-6 activates multiple signaling pathways that culminate in the induction of genes involved in growth, hepatocyte-specific metabolic functions, and the acute-phase response (13).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Heinrich, 1990, Biochem J source

      The section on IL-6-responsive elements in acute-phase protein genes reports IL-6-induced gene transcription, and the Actions section describes increased acute-phase protein synthesis in human hepatocytes. But the Signal transduction section says the underlying mechanisms were still unknown; the cited passages do not establish multiple signaling pathways or induction of genes for hepatocyte growth and specific metabolic functions. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    When IL-6 binds to its receptor complex composed of IL-6R and a gp130 homodimer, a cascade of signaling events is initiated, most notably the Jak/STAT pathway.

    “When IL-6 binds to its receptor complex composed of a specific receptor subunit, the IL-6 receptor (IL-6R), and a gp130 homo dimer, a cascade of signaling events is initiated, most notably the Jak/STAT pathway (14,15).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [14] Heinrich, 1998, Biochem J source
    • cites [15] Imada, 2000, Mol Immunol source

  • May combine two claims.

    Premisecitation

    The levels of TNF and IL-6 increase after PH, with the peak of TNF circulating levels preceding the peak levels of IL-6.

    “The levels of these cytokines increase after PH, with the peak of TNF circulating levels preceding the peak levels of IL-6 (8,10,11).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Yamada, 1997, Proc Natl Acad Sci USA source
    • cites [10] Trautwein, 1996, Gastroenterology source
    • cites [11] Akerman, 1992, Am J Physiol source

  • May combine two claims.

    Premisecitation

    OSM, LIF, and CT-1 have been implicated in liver functions such as development, hepatocyte differentiation, or inflammation, but have not yet been examined in liver regeneration.

    “These cytokines have been implicated in liver functions such as development, hepatocyte differentiation, or inflammation (31)(32)(33), but have yet to be examined in liver regeneration.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [31] Miyajima, 2000, Cytokine Growth Factor Rev source
    • cites [32] Peters, 1995, FEBS Lett source

      The Introduction and Results and discussion link CT-1, LIF, and OSM to hepatocyte acute-phase responses associated with inflammation. The paper does not address liver development or hepatocyte differentiation, and although it does not study liver regeneration, it does not establish that these cytokines had yet to be examined in that setting. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [33] Omori, 1996, Lab Invest

  • May combine two claims.

    Premisecitation

    Nascent SOCS-3 blocks the activation of STAT-3 by binding to the receptor complex via gp130 at tyrosine 759 and/or by binding and inhibiting Jak2 activity.

    “In the first mechanism, nascent SOCS-3 blocks the activation of STAT-3 by binding to the receptor complex via gp130 at tyrosine 759 (34,35) and/or by binding and inhibiting Jak2 activity (36).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [34] Schmitz, 2000, J Biol Chem source
    • cites [35] Nicholson, 2000, Proc Natl Acad Sci USA source
    • cites [36] Krebs, 2000, J Cell Sci source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Possible tyrosine phosphatases include an unidentified nuclear tyrosine phosphatase activity that inactivates IFN-gamma-stimulated STAT-1 and the SH2-containing phosphatases SHP-1 and SHP-2, which regulate cytokine signals in other tissues.

    “Possible tyrosine phosphatases include an unidentified nuclear tyrosine phosphatase activity that has been reported to inactivate IFN-γ-stimulated STAT-1 (37) and the SH2-containing phosphatases, SHP-1 and SHP-2, which regulate cytokine signals in other tissues (38).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [37] Haspel, 1999, Proc Natl Acad Sci USA source
    • cites [38] Feng, 1999, Exp Cell Res source

  • May combine two claims.

    Premisecitation

    Constitutive expression or ablation of SOCS-3 results in embryonic death.

    “These expression systems require conditional expression of SOCS-3 within the parenchymal cells of the liver since constitutive expression or ablation results in embryonic death (40).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [40] Marine, 1999, Cell source

  • May combine two claims.

    Findingcitation

    Robust STAT-3 DNA-binding activity is detected by 2 hours and rapidly disappears between 3 to 6 hours after PH.

    “As has been demonstrated previously (8, 9, 16), robust STAT-3 DNA-binding activity is detected by 2 hours and rapidly disappears between 3 to 6 hours.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Yamada, 1997, Proc Natl Acad Sci USA source
    • cites [9] Cressman, 1996, Science source
    • cites [16] Cressman, 1995, Hepatology source

  • May combine two claims.

    Findingown data

    STAT-3 tyrosine 705 phosphorylation is first detected by 2 hours after PH and decreases to background levels by 8 hours.

    “STAT-3 tyrosine 705 phosphorylation is first detected by 2 hours after surgery and decreases to background levels by 8 hours (Figure 1a, top).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Phosphorylation of serine 727 of STAT-3 can be weakly detected, but the signal is variable.

    “Phosphorylation of serine 727 of STAT-3 can be weakly detected (Figure 1a, middle), but the signal is variable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Increased SOCS-3 protein levels were first detected by 2 hours with sustained expression until 8 and 10 hours after PH.

    “Increased SOCS-3 protein levels were first detected by 2 hours with sustained expression until 8 and 10 hours (Figure 2c, top).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Both STAT-3 activity and SOCS-3 protein are no longer detectable by 8 hours after PH.

    “Both STAT-3 activity and SOCS-3 protein are no longer detectable by 8 hours after PH.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The low level of tyrosine 705 phosphorylation of STAT-3 in the KO mice after PH correlates with weak STAT-3 DNA binding and weak induction of SOCS-3.

    “The low level of tyrosine 705 phosphorylation of STAT-3 in the KO mice after PH correlates with weak STAT-3 DNA binding (Figure 4b) and weak induction of SOCS-3 (Figure 3a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TNF injection also transiently induces CIS mRNA and SOCS-2 and SOCS-1 mRNAs.

    “TNF injection also transiently induces CIS mRNA (Figure 5b) and SOCS-2 and SOCS-1 mRNAs (data no shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    IL-6 injection also induces SOCS-1, SOCS-2, and CIS mRNA expression, a pattern not seen after PH.

    “However, IL-6 injection also induces SOCS-1, -2, and CIS mRNA expression, a pattern not seen after PH.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SOCS-3 message is first detected at 1 hour and disappears rapidly after TNF injection.

    “SOCS-3 message is first detected at 1 hour and disappears rapidly (Figure 5a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CIS is induced in the liver of IL-6 KO mice but not in TNF-R1 KO mice after TNF injection.

    “In contrast to SOCS-3, CIS is induced in the liver of IL-6 KO mice but not in TNF-R1 KO mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SOCS-3 mRNA is induced by 1 hour and rapidly declines by 2 hours after IL-6 injection.

    “SOCS-3 mRNA is induced by 1 hour and rapidly declines by 2 hours after IL-6 injection (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SOCS-3 protein is detectable after IL-6 injection but not after TNF injection.

    “SOCS-3 protein can be detected after IL-6 injection, but not after TNF injection (Figure 6c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SOCS-3 protein was detected in WT by immunoblot analysis, but not in IL-6 KO liver.

    “Moreover, SOCS-3 protein was detected in WT by immunoblot analysis, but not in IL-6 KO liver (Figure 3c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Both hepatocytes in vivo and in culture respond to IL-6 treatment in a similar manner, with only STAT-3 homodimers (SIF A) found.

    “Moreover, both hepatocytes in vivo and in culture respond to IL-6 treatment in a similar manner; that is, only STAT-3 homodimers (SIF A) are found (unpublished observations and ref. 30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Bode, 1999, FEBS Lett source

  • May combine two claims.

    Findingown data

    PH induced CIS and SOCS-2 levels only between fourfold and tenfold compared with controls, and in some experiments no induction was detected.

    “PH induced CIS and SOCS-2 levels only between fourfold and tenfold compared with controls, and in some experiments no induction was detected.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A 40-to 50-fold increase of SOCS-3 mRNA is seen at 2 hours and is sustained for 4 hours when the levels start declining at 8 hours after PH and return to baseline levels by 24 hours.

    “A 40-to 50-fold increase of SOCS-3 mRNA is seen at 2 hours and is sustained for 4 hours when the levels start declining at 8 hours after PH and return to baseline levels by 24 hours (Figure 2b).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several mechanisms are known to be involved in inactivating STAT pathways: SHP-1 and -2, PIAS, and SOCS.

    “To date, there are several mechanisms known to be involved in inactivating STAT pathways: the SH2-containing protein tyrosine phosphatases, SHP-1 and -2, the protein inhibitors of activated STATs (PIAS), and the suppressors of cytokine signaling (SOCS) (reviewed in refs.4,[17][18][19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites reviewed in refs.4,[17][18][19]

      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). May combine two claims.

    Premisecitation

    Depending on the tissue or cell type, the mRNA is short lived and the half-life of the SOCS protein is between 1 to 2 hours.

    “Depending on the tissue or cell type, the mRNA is short lived and the half-life of the SOCS protein is between 1 to 2 hours (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Siewert, 1999, Eur J Biochem source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    STAT-3 is activated after PH as the result of increased IL-6 levels, implicating both IL-6 and STAT-3 as part of the priming mechanism for hepatocyte proliferation.

    “It has been demonstrated previously that STAT-3 is activated after PH as the result of increased IL-6 levels (8, 9, 16), implicating both IL-6 and STAT-3 as part of the priming mechanism for hepatocyte proliferation.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Yamada, 1997, Proc Natl Acad Sci USA source
    • cites [9] Cressman, 1996, Science source
    • cites [16] Cressman, 1995, Hepatology source

  • May combine two claims.

    Interpretationown data

    STAT-3 tyrosine 705 phosphorylation and DNA-binding activity are transiently activated after surgery.

    “Thus, STAT-3 tyrosine 705 phosphorylation and DNA-binding activity are transiently activated after surgery.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Preoperative injection of IL-6 rescues the defects in hepatocyte proliferation and returns a number of early signal transduction pathways to levels seen in wild-type mice.

    “Preoperative injection of IL-6 not only rescues the defects in hepatocyte proliferation, but returns a number of early signal transduction pathways to levels seen in wild-type (WT) mice (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Cressman, 1996, Science source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    For regeneration to take place, normally quiescent hepatocytes must gain proliferative capacity and undergo a transition from G0 to G1, a process known as priming.

    “For regeneration to take place, normally quiescent hepatocytes must gain proliferative capacity and undergo a transition from G0 to G1, a process known as priming (1,6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Fausto, 2000, J Hepatol source
    • cites [6] Steer, 1995, FASEB J source

  • May combine two claims.

    Study design and conductown data

    Specific STAT-3 binding was confirmed by supershift analysis with a specific STAT-3 Ab, and competition with a 200-fold excess of unlabeled probe confirmed that only STAT-3 bound to the SIE probe.

    “Specific STAT-3 binding was analyzed by supershift analysis with a specific STAT-3 Ab, and competition with a 200-fold excess of unlabeled probe confirmed that only STAT-3 bound to the SIE probe (Figure 4b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PH appears to selectively upregulate SOCS-3 and not other members of the SOCS family.

    “Thus, PH appears to selectively upregulate SOCS-3 and not other members of the SOCS family.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The induction of SOCS-3 correlates with the activation and inactivation of STAT-3, suggesting that in liver regeneration SOCS-3 participates in a negative-feedback loop to decrease STAT-3 activity.

    “Importantly, the induction of SOCS-3 correlates with the activation and inactivation of STAT-3, suggesting that in liver regeneration SOCS-3 participates in a negative-feedback loop to decrease STAT-3 activity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The STAT family of transcription factors mediates the induction of SOCS genes.
    • Rests on an assumption: SOCS proteins participate in a feedback loop to inhibit STAT activity as well as cytokine signals.

  • May combine two claims.

    Interpretationown data

    SOCS-3 is the major SOCS family member induced after PH, and the induction of SOCS-3 mRNA and protein levels is transient.

    “Taken together, these results indicate that SOCS-3 is the major SOCS family member induced after PH, and the induction of SOCS-3 mRNA and protein levels is transient.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    IL-6 injection bypasses the lack of TNF and IL-6 signaling and induces all SOCS molecules examined in murine liver.

    “In summary, IL-6 injection bypasses the lack of TNF and IL-6 signaling and induces all SOCS molecules examined in murine liver.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    SOCS mRNA levels were normalized to cyclophilin levels at each time point.

    “SOCS mRNA levels were normalized to cyclophilin levels at each time point.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The blots were stripped and reprobed with β-actin to ensure equal loading.

    “The blots were stripped and reprobed with β-actin to ensure equal loading (Figure 2c, bottom).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    SOCS-3 induction is dependent on IL-6 and, perhaps, TNF-signaling pathways.

    “These results suggest that SOCS-3 induction is dependent on IL-6 and, perhaps, TNF-signaling pathways.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Sham operation was performed as laparotomy, otherwise sham-operated mice were treated the same as PH mice.

    “Laparotomy was performed as the sham operation, otherwise the sham-operated mice were treated the same as PH mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    While TNF can induce SOCS-3, this induction is much weaker and more transient compared with the induction following PH.

    “These results suggest that while TNF can induce SOCS-3, this induction is much weaker and more transient compared with the induction following PH.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Other mechanisms such as PIAS may also play a role in inhibiting early cytokine signaling during PH.

    “Other mechanisms such as PIAS (39) that downregulate cytokine signaling in other cells may also play a role in inhibiting early cytokine signaling during PH.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Shuai, 2000, Oncogene source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Existing, activated (tyrosine-phosphorylated) pools of STAT-3 may be inactivated by dephosphorylation through the actions of a tyrosine phosphatase.

    “Secondly, existing, activated pools of STAT-3 (i.e., tyrosine phosphorylated) may be inactivated by dephosphorylation through the actions of a tyrosine phosphatase.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The priming phase of hepatocyte replication probably ends at 5-6 hours after PH, perhaps even earlier.

    “The priming phase of hepatocyte replication probably ends at 5-6 hours after PH, perhaps even earlier.”
    Quote in the paperNot a substantial claim
42 of 42

  • The paper relies on this without support.

    The STAT family of transcription factors mediates the induction of SOCS genes.

    “Importantly, the STAT family of transcription factors mediates the induction of SOCS genes.”

  • The paper relies on this without support.

    SOCS proteins participate in a feedback loop to inhibit STAT activity as well as cytokine signals.

    “Thus, SOCS proteins participate in a feedback loop to inhibit STAT activity as well as cytokine signals.”

  • The paper relies on this without support.

    The mechanisms that downregulate or turn off the cytokine signaling pathways during liver regeneration are unclear.

    “However, the mechanisms that downregulate or”

  • The paper relies on this without support.

    TNF levels increase after PH, activating NF-kappaB, which upregulates IL-6 mRNA, resulting in elevated serum levels of IL-6.

    “TNF levels increase after PH, activating the transcription factor, NF-κB, which in turn upregulates IL-6 mRNA, resulting in elevated serum levels of IL-6.”

  • The paper relies on this without support.

    IL-6 stimulates hepatic STAT-3 by inducing phosphorylation at tyrosine 705, which allows nuclear translocation and DNA binding.

    “IL-6 stimulates hepatic STAT-3 by inducing phosphorylation at tyrosine 705, which allows nuclear translocation and DNA binding.”

  • The paper relies on this without support.

    STAT-3 induces SOCS-3 mRNA, leading to an increase in SOCS-3 protein levels, which downregulate IL-6-stimulated STAT-3.

    “STAT-3 also induces SOCS-3 mRNA leading to an increase in SOCS-3 protein levels, which downregulate IL-6-stimulated STAT-3.”
6 of 6

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.

  • SOCS-3 protein is both present and absent at 8 hours

    Minor

    The results describe sustained SOCS-3 protein expression through 8 and 10 hours after PH, whereas the discussion says it is no longer detectable by 8 hours.

  • Figure 5 caption contradicts CIS induction in IL-6 KO mice

    Minor

    The caption says TNF induces neither SOCS-3 nor CIS in IL-6 KO liver, but the results state that CIS is induced in those mice.

  • STAT-3 serine phosphorylation site differs between methods and results

    Minor

    The methods identify an antibody against STAT-3 phosphoserine 729, but the results identify the measured signal as phosphorylation of serine 727.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Plumpe, 1999, Ital J Gastroenterol Hepatol, 31, 235
  2. Akerman, 1992, Am J Physiol, 263, G579
  3. Omori, 1996, Lab Invest, 75, 15

Cited by

Sorted by citations

Related

Authors
Campbell, J. S., Prichard, L., Schaper, F., Schmitz, J., Stephenson-Famy, A., Rosenfeld, M. E., Argast, G. M., Heinrich, P. C., & Fausto, N.
Affiliations
  • University of Washington (US)
  • RWTH Aachen University (DE)
Corresponding author
Fausto, Nelson
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2001-05-15
Volume
107
Issue
10
Pages
1285-1292
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci11867
PMC
PMC209297
OpenAlex
W2013349369
Cited by
156
References
42
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 3 · 2019: 4 · 2018: 2 · 2017: 8 · 2016: 4 · 2015: 4 · 2014: 8 · 2013: 9 · 2012: 9
FWCI
4.48
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • RWTH Publications (RWTH Aachen) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft
  • National Institutes of Health (1r43ai023226-01, CA23226)
  • National Cancer Institute (R01 CA074131, R37 CA023226, CA 74131, R01CA023226)
  • National Institute of Allergy and Infectious Diseases (AI-23226)
  • National Institute of Diabetes and Digestive and Kidney Diseases (F32 DK09920-01, F32DK009920)
  • National Institute of Environmental Health Sciences (T32-ES07032-23, T32ES007032)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
suppressor of cytokine signaling, SOCS3, SOCS1, SOCS2, liver regeneration, partial hepatectomy, interleukin-6, TNF-α, STAT3 signaling, tyrosine phosphorylation, IL-6 knockout mice, TNF receptor 1
MeSH terms
Suppressor of Cytokine Signaling 3 Protein, Animals, DNA-Binding Proteins, Gene Expression Regulation, Hepatectomy, Liver Regeneration, Proteins, Repressor Proteins, Transcription Factors, Tumor Necrosis Factor-alpha, Signal Transduction, Trans-Activators, Antigens, CD, Interleukin-6, Receptors, Tumor Necrosis Factor, Mice, Knockout, Receptors, Tumor Necrosis Factor, Type I, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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