Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice

Cressman, Drew E.; Greenbaum, Linda E.; DeAngelis, Robert A.; Ciliberto, Gennaro; Furth, Emma E.; Poli, Valeria; Taub, Rebecca

doi:10.1126/science.274.5291.1379

Cited by 1,415 publications

(1,345 citation statements)

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“…Several publications have documented that both oncogenic Ras and oncogenic Raf can stimulate proliferation and suppress differentiation in SV40 virus immortalized hepatocytes [9,10]. Since both oncogenic Ras and oncogenic Raf will cause potent activation of the MAP kinase cascade, these data would initially appear to be in conflict with our results.…”

Section: Discussioncontrasting

confidence: 76%

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The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

Tombes

Auer

Mikkelsen

et al. 1998

Biochemical Journal

179

155

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Bailie et al. [In Vitro Cell Dev. Biol. (1992) 28A, 621-624] reported that primary cultures of rat hepatocytes possess low affinity binding sites for nerve growth factor (NGF). NGF treatment of primary cultures of rat hepatocytes with a maximally effective concentration of NGF (20 ng/ml, 0.8 nM) caused acute phasic activation of Raf-1 and p42MAPkinase, and a smaller sustained activation of B-Raf. The transient increase in Raf-1 and p42MAPkinase activity returned to baseline within ~ 30 min. NGF treatment of hepatocytes did not induce expression of cyclin dependent kinase (cdk) inhibitor proteins, but instead stimulated cdk2 activity and increased [3H]thymidine incorporation into DNA. In contrast to hepatocytes, NGF treatment of PC12 pheochromocytoma cells caused large sustained activations of B-Raf and p42MAPkinase, and a lower phasic activation of Raf-1. The sustained activations of B-Raf and p42MAPkinase were for more than 5 h. Treatment of PC12 cells with NGF increased p21Cip1/WAF-1 expression, reduced cdk2 activity and inhibited DNA synthesis, the opposite to the effects of NGF treatment of hepatocytes. However when p42MAPkinase was chronically activated in hepatocytes, via infection with an inducible oestrogen receptor-Raf-1 fusion protein, expression of p21Cip-1/WAF1 and p16INK4a cdk inhibitor proteins increased, cdk2 activity decreased, and DNA synthesis decreased. Equally, treatment of hepatocytes with 50 mM ethanol elevated the basal activity of p42MAPkinase and temporally extended the ability of NGF treatment to activate p42MAPkinase. Ethanol and NGF co-treatment increased expression of p21Cip-1/WAF1 and p16INK4a cdk inhibitor proteins and decreased hepatocyte DNA synthesis. These data demonstrate that NGF can cause either acute/phasic or sustained activation of the MAP kinase cascade in different cell types. Acute activation of the MAP kinase cascade correlated with increased DNA synthesis. In contrast, sustained activation of the MAP kinase cascade correlated with increased expression of cdk inhibitor proteins, a reduction in cdk activity, and an inhibition of DNA synthesis. These data suggest a general mechanism exists where acute activation of the MAP kinase cascade promotes G1 progression/S phase entry and that chronic activation of the MAP kinase cascade inhibits this process.

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Section: Discussioncontrasting

confidence: 76%

“…Partial hepatectomy or acute dissociation by collagenase treatment and primary culture of hepatocytes triggers their entry into the cell cycle [1][2][3][4][5][6][7][8][9][10]. Maximal DNA synthesis in i o occurs 12-36 h post partial hepatectomy and within 5-7 days the liver has regained its original mass [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

Tombes

Auer

Mikkelsen

et al. 1998

Biochemical Journal

179

155

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“…Mere A20 heterozygous knockdown transformed PH from a well-tolerated procedure to one with more than 40% lethality, uncovering an otherwise unsuspected phenotype in HET mice. Remarkably, lethality in HET mice topped that of IL-6 KO, 30 TNF-receptor-1 KO 31 and conditional hepatocyte-specific STAT3 KO, 32 qualifying A20 among the most potent key physiologic regulators of LR.…”

Section: Discussionmentioning

confidence: 99%

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

et al. 2015

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Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (440%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of 41000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver proregenerative therapies. Humans and mice restore their liver mass within 2 weeks of surgical, viral or toxic parenchymal loss via compensatory regrowth, referred to as liver regeneration (LR). 1,2 Adequate LR is contingent upon maintaining a minimum healthy residual liver mass without which hepatocyte proliferation is stunned, resulting in hepatic failure. In liver transplantation (mainly living donor liver transplantation), 'small-for-size' syndrome illustrates this outcome. 3 Incremental 78% and 87% hepatectomy in mice reproduces this syndrome, causing 50% and 100% lethality, respectively. 4 Despite considerable knowledge characterizing the molecular basis of LR, better understanding of this process's shortcomings in the face of extensive resection and/or damage is required for uncovering therapie...

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“…Defects in this pathway, for example, STAT-3 deficiency in macrophages and neutrophils, lead to the constitutive activation of these cells and result in progression to chronic inflammation (39) similar to the phenotype of Plg -/-mice in the current study. In studies of liver wound healing, large areas of necrosis can be found in the liver of both IL-6 -/-and Plg -/-mice (40,41). In the current study, we found that levels of IL-6 and IL-10 expression are higher in infected joints of Plg ϩ/ϩ mice than in those of Plg -/-mice, and supplementation with human plasminogen increased the expression of IL-6 in the infected knee joints.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus–induced arthritis

Guo¹,

Li²,

Hagström³

et al. 2008

Arthritis & Rheumatism

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Objective. To assess the functional roles of plasmin in a murine model of Staphylococcus aureus-induced bacterial arthritis.Methods. Bacterial arthritis was induced in plasminogen-deficient (Plg -/-) and wild-type (Plg ؉/؉ ) littermates by local injection of 1 ؋ 10 6 colony-forming units of S aureus into the knee joints. Human plasminogen was administered to Plg -/-mice on days 0-7 or days 7-14. Antibiotic treatment was administered to Plg -/-mice on days 7-14. Bacteria counts and histologic, immunohistochemical, and Western blot analyses were performed.Results. In Plg ؉/؉ mice, S aureus counts had declined within 2 days, and by day 28 the bacteria had been completely eliminated. However, S aureus was still detectable in all injected joints from Plg -/-mice, and bacteria counts were 27 times higher than the amount injected on day 0. The extent of macrophage and neutrophil recruitment to the infected joints was comparable for Plg ؉/؉ and Plg -/-mice on days 1, 7, and 14. The activation of these inflammatory cells appeared to be impaired in Plg -/-mice, however. Treatment of Plg -/-mice with antibiotic (cloxacillin) resulted in successful killing of the bacteria, but the necrotic tissue remained in the infected joints. When human plasminogen was given intravenously to Plg -/-mice daily for 7 days, bacterial clearance was greatly improved as compared with their untreated counterparts, and the amount of necrotic tissue in the joint cavity was dramatically reduced. The expression of interleukin 6 (IL-6) and IL-10 was higher in Plg ؉/؉ mice than in Plg -/-mice during bacterial arthritis.Conclusion. Our findings indicate that plasmin plays a pluripotent role in protecting against S aureusinduced arthritis by activating inflammatory cells, killing bacteria, removing necrotic tissue, and enhancing cytokine expression.Staphylococcus aureus is the microorganism most frequently associated with bacterial arthritis (1,2), which results in synovial inflammation, cartilage and bone destruction, and eventually, joint deformity (3). The plasminogen activator (PA) system is a general proteolytic system that has been suggested to play an important role in the development of different types of arthritis (4-6). Plasminogen can be activated to the broadspectrum protease plasmin by either of the 2 physiologic PAs, tissue-type PA (tPA) or urokinase-type PA (uPA). In addition to its function in fibrinolysis, plasmin(ogen) plays a role in degradation of the extracellular matrix (ECM) and in tissue remodeling during many physiologic and pathologic processes, such as wound healing (7), tumor cell invasion, angiogenesis, and rheumatoid arthritis (RA) (8). There is some evidence that plasmin can also induce proinflammatory responses independently of its proteolytic properties (9).A number of pathogenic microorganisms have been shown to bind plasminogen (10-12). The subsequent activation of plasminogen to plasmin may contribute to the virulence of these microorganisms (13). However, during bacterial arthritis, plasmin may also be of importance...

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Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice

Cited by 1,415 publications

References 39 publications

The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus–induced arthritis

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