- Email: [email protected]
91 TOLL LIKE RECEPTOR 4 ANTAGONIST PREVENTS ACETAMINOPHEN INDUCED ACUTE LIVER FAILURE IN MICE: A NOVEL THERAPEUTIC STRATEGY
ORAL PRESENTATIONS or Cyclophosphamide+Naproxen nearly doubled the hypobilirubinemic effect of hepatocyte transplantation in Gunn rats. The window period for transplanting hepatocytes after treatment with Cyclophosphamide is 24–48 h. These findings may be relevant in hepatocyte transplantation-based therapies of liver-based inherited metabolic disorders. 89 DELETION OF TRAIL ON NK CELLS IS ASSOCIATED WITH EXCESSIVE HEPATIC ISCHEMIA-REPERFUSION INJURY IN MICE R. Fahrner1 , M. Trochsler1 , N. Corazza2 , T. Brunner2 , N. Graubardt1 , A. Keogh1 , D. Candinas1 , D. Stroka1 , G. Beldi1 . 1 Department of Visceral Surgery and Medicine, University Hospital, 2 Division of Immunopathology, Institute of Pathology, University of Bern, Bern, Switzerland E-mail: [email protected] Background and Aims: Ischemia-reperfusion injury (IRI) is a key factor that contributes to early and late dysfunction of liver grafts. Recent studies reveal that natural killer (NK) cells play an important role in liver injury post IRI. We hypothesized that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand with high expression on NK cells significantly impacts IRI. Methods: C57/BL6 wild-type and TRAIL knock-out mice (TRAIL−/−) were subjected to hepatic IRI for one hour. Adoptive transfer of wild-type and TRAIL−/− NK cells was performed into RAG2/common gamma null mice that lack T, B and NK cells. Liver injury was assessed by hepatic neutrophil infiltration, alanine aminotransferase (ALT), aspartate transaminase (AST), hepatic neutrophil activation by myeloperoxidase (MPO) activity. NK cell subsets of the ischemic liver lobe were analysed by flow cytometry. NK cell cytotoxicity and interferon gamma secretion were performed in vitro studies. Results: TRAIL−/− mice exhibit significantly more hepatic damage assessed by AST and ALT levels 24 hours post IRI compared to wildtype mice. Adoptive transfer of TRAIL−/− NK cells to Rag2/common gamma-null mice was associated with significantly increased IRI compared to transfer with wild-type NK cells. Hepatic neutrophil activation was significantly increased in TRAIL−/− compared to wild-type mice. Staining for CD107a, a marker of degranulation and cytotoxicity on NK cells was significantly elevated in ischemic liver lobes of TRAIL−/− compared to wild-type mice. In vitro NK cell cytotoxicity to a Yac-1 cancer cell line was significantly increased in sorted TRAIL−/− NK cells compared to wild-type NK cells. Systemic cytokine levels (TNF alpha, IL-1beta, IL-6) and interferon gamma secretion of NK cells after stimulation with IL-12/IL-18 in vitro were not significantly different between the groups. Conclusions: These results show that expression of TRAIL on NK cells is protective in a murine model of hepatic IRI via the modulation of NK cell mediated cytotoxicity. 90 CYCLOSPORINE AND TACROLIMUS HAVE DIFFERENT INHIBITORY EFFECTS ON TOLL-LIKE RECEPTOR SIGNALLING IN HEPATITIS C RECURRENCE POST LIVER TRANSPLANTATION J. Howell1,2,3 , R. Sawhney1,2,3 , N. Skinner1 , D. Ratnam1 , P. Angus2,3 , P. Gow2,3 , K. Visvanathan1 . 1 Innate Immune Laboratory, Monash Medical Centre, Monash University, Clayton, 2 Medicine, University of Melbourne, Parkville, 3 Gastroenterology, Austin Health and Victorian Liver Transplant Unit, Heidelberg, VIC, Australia E-mail: [email protected] Background: Hepatitis C (HCV) recurrence post liver transplant follows a more aggressive course than pre-transplantation and the mechanisms remain poorly understood. Toll-like receptors (TLRs) are critical to innate immune antiviral responses. The interplay between TLR function and immunosuppressive drugs and how this may affect HCV recurrence post transplant is unknown.
Methods: Peripheral blood mononuclear cells (PBMCs) from 83 HCV post liver transplant patients, 53 non-HCV post transplant controls (matched for sex, race and time post transplant) and 10 healthy controls were stimulated with TLR specific ligands LPS (TLR4), P3C (TLR2), PIC (TLR3), R848 (TLR7/8) and CpG (TLR9) for 24 hrs. Production of interleukin 6 (IL-6), tumour necrosis factor (TNF) and interferon alpha (IFNa) was then measured using ELISA. Flow cytometry was used to determine intracellular cytokine production by monocytes, NK, NKT and T cells. Results were compared between groups using Mann-Whitney and Spearman correlation. Results: Cyclosporine levels correlated with reduced TLR3-induced IFNg production by NK cells (NK cells p = 0.011, CD56bright NK cells p = 0.017) and T cells (p = 0.049). Cyclosporine levels also correlated with reduced TLR3-induced monocyte IL-6 (p = 0.028) and TNF (p = 0.070) production. Cyclosporine level correlated positively with T cell frequency (p = 0.040). In contrast, tacrolimus levels correlated inversely with TLR4induced PBMC IL-6 production (p = 0.030), TLR3-induced TNF production by PBMCs (p = 0.027) and TLR7/8-induced NK cell TNF (NK cells p = 0.009, CD56dim NK cells p = 0.013). Tacrolimus levels correlated inversely with NKT cell frequency (p = 0.032). Conclusion: NK cells and monocytes have impaired TLR3-induced cytokine production that varied with increasing cyclosporine level. In contrast, tacrolimus levels correlated inversely with TLR4induced IL-6 by PBMCs, TLR3-induced TNF from monocytes, and TLR7/8 induced TNF from NK cells. These data demonstrate important relationships between TLR function and calcineurin inhibitor levels that may contribute to aggressive HCV recurrence post liver transplant. Importantly, our data also suggest that tacrolimus and cyclosporine have different effects on innate immune signaling especially in the context of post transplant HCV recurrence. 91 TOLL LIKE RECEPTOR 4 ANTAGONIST PREVENTS ACETAMINOPHEN INDUCED ACUTE LIVER FAILURE IN MICE: A NOVEL THERAPEUTIC STRATEGY N. Shah, D. Dhar, M. Jover, N.A. Davies, R.P. Mookerjee, R. Jalan. UCL, Institute of Hepatology, London, UK E-mail: [email protected] Background and Aim: Without transplantation, about 40% of patients with acute liver failure (ALF) die. Its treatment is an unmet need. Unregulated inflammation plays an important role in the pathogenesis. Our hypothesis is that Toll like receptor 4 (TLR 4) is critical in the progression of inflammation in ALF. The aims of the study were to determine whether 1) administration of a novel TLR4 antagonist to an APAP model of ALF in mice would prevent liver injury. 2) TLR4 antagonist in ALF prolongs survival. 3) TLR4 KO are protected from the liver injury induced by acetaminophen (APAP). Method: Study 1: 3 groups of CD1 mice were studied (n = 6 in each group) Naive, APAP, 500 mg/kg single dose IP after overnight fasting). APAP+TLR4 antagonist (STM28, OsakauniversityJapan); 20ug IP, 1 hour prior to administration of APAP and 6 hours later). Study 2: 3 groups of C57BL/6 mice were studied (n = 6) in each group. Naive, APAP (500 mg/kg single dose IP), APAP+TLR4 antagonist (IAXO (Innaxon) 3 mg/kg, 1 hour prior to administration of APAP and 6 hours later). Study 3: C57BL/6 TLR4 KO were administered APAP 500 mg/Kg and the respective Naive controls were administered saline. Biochemistry was measured using COBAS integra, Cytokines in plasma and tissue homogenate of liver, kidney and brain were measured using ELISA bead array. Brain water was measured using the dry-wet weight method. Results: Both the TLR4 antagonist’s (STM28 and IAXO compound) reduced the plasma liver enzymes, ammonia and creatinine to the control level. The increase in the plasma TNF-a induced
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ORAL PRESENTATIONS by APAP (45±3.2) was attenuated following TLR4 antagonist (20±2.3) (p < 0.01). This was associated with a reduction in brain water (p < 0.01). Both the TLR4 antagonists significantly reduced pericentral necrosis of the liver. Both these interventions showed an improvement in the survival as using the log rank test (p < 0.02). TLR4 KO mice treated with APAP were protected from liver necrosis and had significantly better survival than wild type controls (p < 0.002). Conclusion: These data provides evidence for an important of TLR4 in APAP induced ALF and provide the rationale for a clinical trial of this strategy in ALF. 92 THE HEPATIC INFLAMMATORY MICROENVIRONMENT INDUCES ENDOTOXIN TOLERANT MONOCYTES IN ACETAMINOPHEN-INDUCED LIVER FAILURE C.G. Antoniades1,2 , V. Zingarelli2 , L. Possamai1 , R. Mitry2 , W. Bernal2 , G. Auzinger2 , N. Heaton2 , A. Quaglia2 , Y. Ma2 , D. Vergani2 , J. Wendon2 , M. Thursz1 . 1 Section of Hepatology, Imperial College London, 2 Institute of Liver Studies, King’s College London, London, UK E-mail: [email protected] Background: Endotoxin-tolerant monocytes (ET), typified by reduced monocyte HLA-DR expression and attenuated proinflammatory responses, are described in human acetaminopheninduced liver failure (AALF) and may be induced by antiinflammatory mediators (e.g. IL-10, secretory leucocyte protease inhibitor [SLPI]) through toll-like receptor-4 (TLR-4) and STAT-3 signalling pathways. In AALF, the inflamed liver is characterised by elevations in anti-inflammatory/tissue repair cytokines. Aims: Using ex-vivo and in-vitro cell culture systems, we sought to investigate the effects of the hepatic inflammatory microenvironment on monocyte/macrophage function. Methods: Using Phosphoflow, ex-vivo monocyte NF-kBp65 and STAT-3 signalling was assessed in 10 AALF patients and 10 healthy controls (HC). Trans-hepatic (portal vein [PV]), hepatic vein [HV])) serum TNF-a, IL-10, SLPI (n = 5) were measured at time of transplantation. Serum (AALF [n = 34]; HC [n = 15]) and hepatic (AALF [n = 7]; HC [n = 8]) levels of TNF-a, IL-10 and SLPI were measured (pg/ml). Monocyte phenotype/function was assessed by in purified CD14+ monocytes from HC in five different tissue homogenates derived from AALF, normal liver tissue (NL) and in culture medium (CM) following 48 hours. Results: Following TLR-4 stimulation, AALF patients had reduced NF-kBp65 ratio of activation (0.8 vs 1.6; p = 0.001) and higher STAT-3 MFI compared to HC (600 vs 232; p = 0.02). AALF patients had significantly higher concentrations of IL-10 (serum: 170 vs 40; hepatic: 2 vs 0.6; p < 0.02), SLPI (serum: 71200 vs 43310; hepatic: 442 vs 116; p < 0.001) compared to HC. A transhepatic (HV>PV) gradient was seen for IL-10 and SLPI but not for TNF-a (Figure 1). In vitro, exposure to AALF homogenate induced an antiinflammatory, CD36highHLA-DRlow CD14+CD16+ macrophage phenotype (78.5% vs 63%; p = 0.03) (representative cell culture experiment shown in Figure 2).
Figure 1. Transhepatic levels of IL-10 and SLPI in acetaminophen-induced ALF patients. S40
Figure 2. Representative cell culture experiment demonstrating in vitro effects of AALF microenvironment on CD14+ monocytes.
Conclusion: In AALF, circulating monocytes show modulations in intracellular signalling pathways compatible with ET. Our data indicate that the hepatic microenvironment and production of anti-inflammatory mediators could be pivotal mediators of ET and increase the risk of infection in AALF.
Parallel Session: NASH AND ASH
93 INTERLEUKIN-10 RELEASED BY M2 KUPFFER CELLS PROMOTES M1 KUPFFER CELL APOPTOSIS: A NOVEL PROTECTIVE MECHANISM AGAINST ALCOHOLIC LIVER DISEASE J. Wan1 , M. Benkdane1 , F. Teixeira-Clerc1 , V. Deveaux1 , A. Louvet1 , F. Lafdil1 , F. Pecker1 , A. Mallat1,2 , S. Lotersztajn1 , C. Pavoine1 . 1 INSERM U955 e´quipe 17, Hˆ opital Henri-Mondor, Universit´e Paris-Est Cr´eteil, 2 Department of Hepatology and Gastroenterology, AP-HP, Groupe Henri Mondor-Albert Chenevier, Cr´eteil, France E-mail: [email protected] Aims: Activation of Kupffer cells towards a pro-inflammatory (M1) phenotype is a critical step in the deleterious process initiating alcohol-induced liver injury. We investigated whether favoring antiinflammatory (M2) polarization of Kupffer cells may protect against alcoholic liver disease. Methods: C57 Bl6/J mice were compared to BALB/c Th2-prone mice in a model of chronic alcohol exposure in which Kupffer cells are activated in the absence of inflammatory cell recruitment. M1 and M2 signature was characterized by RT-PCR; M1 and M2-polarized Kupffer cells were identified by iNOS/F4–80 (M1) or CD206/F4–80 (M2) immunohistochemistry or FACS analysis. Apoptosis was evaluated by cleaved caspase-3 labelling. In vitro studies were performed on isolated Kupffer cells, polarized into M1 and M2 by LPS or IL4. Results: in contrast to C57BL6/J mice, BALB/c mice were protected against alcohol-induced liver injury and steatosis. In response to chronic alcohol exposure, Kupffer cells from BALB/c mice displayed a preponderant M2 phenotype whereas Kupffer cells from C57BL6/J mice adopted M1 polarization. Interestingly, predominant M2 polarization was associated with selective apoptosis of M1 Kupffer cells in BALB/c livers. Studies in isolated Kupffer cells demonstrated that exposure of M1 cells to M2 conditioned medium increased cleaved caspase 3 staining of M1 Kupffer cells. Mechanistically, in vivo and in vitro data highlighted the central role of interleukin10 in M2-induced M1 apoptosis. Thus, exposure of M1 polarized macrophages to IL10 triggered their apoptosis. Moreover, anti-IL10 antibodies blunted apoptosis of M1-polarized macrophages elicited by M2 conditioned medium. In keeping with in vitro results, IL10 levels were increased in the livers of alcohol-fed BALB/c mice, as compared to C57BL6/J counterparts. Strikingly, in vivo neutralization of IL10 prevented M1 Kupffer cell apoptosis.
Journal of Hepatology 2012 vol. 56 | S21–S44
Methods: Peripheral blood mononuclear cells (PBMCs) from 83 HCV post liver transplant patients, 53 non-HCV post transplant controls (matched for sex, race and time post transplant) and 10 healthy controls were stimulated with TLR specific ligands LPS (TLR4), P3C (TLR2), PIC (TLR3), R848 (TLR7/8) and CpG (TLR9) for 24 hrs. Production of interleukin 6 (IL-6), tumour necrosis factor (TNF) and interferon alpha (IFNa) was then measured using ELISA. Flow cytometry was used to determine intracellular cytokine production by monocytes, NK, NKT and T cells. Results were compared between groups using Mann-Whitney and Spearman correlation. Results: Cyclosporine levels correlated with reduced TLR3-induced IFNg production by NK cells (NK cells p = 0.011, CD56bright NK cells p = 0.017) and T cells (p = 0.049). Cyclosporine levels also correlated with reduced TLR3-induced monocyte IL-6 (p = 0.028) and TNF (p = 0.070) production. Cyclosporine level correlated positively with T cell frequency (p = 0.040). In contrast, tacrolimus levels correlated inversely with TLR4induced PBMC IL-6 production (p = 0.030), TLR3-induced TNF production by PBMCs (p = 0.027) and TLR7/8-induced NK cell TNF (NK cells p = 0.009, CD56dim NK cells p = 0.013). Tacrolimus levels correlated inversely with NKT cell frequency (p = 0.032). Conclusion: NK cells and monocytes have impaired TLR3-induced cytokine production that varied with increasing cyclosporine level. In contrast, tacrolimus levels correlated inversely with TLR4induced IL-6 by PBMCs, TLR3-induced TNF from monocytes, and TLR7/8 induced TNF from NK cells. These data demonstrate important relationships between TLR function and calcineurin inhibitor levels that may contribute to aggressive HCV recurrence post liver transplant. Importantly, our data also suggest that tacrolimus and cyclosporine have different effects on innate immune signaling especially in the context of post transplant HCV recurrence. 91 TOLL LIKE RECEPTOR 4 ANTAGONIST PREVENTS ACETAMINOPHEN INDUCED ACUTE LIVER FAILURE IN MICE: A NOVEL THERAPEUTIC STRATEGY N. Shah, D. Dhar, M. Jover, N.A. Davies, R.P. Mookerjee, R. Jalan. UCL, Institute of Hepatology, London, UK E-mail: [email protected] Background and Aim: Without transplantation, about 40% of patients with acute liver failure (ALF) die. Its treatment is an unmet need. Unregulated inflammation plays an important role in the pathogenesis. Our hypothesis is that Toll like receptor 4 (TLR 4) is critical in the progression of inflammation in ALF. The aims of the study were to determine whether 1) administration of a novel TLR4 antagonist to an APAP model of ALF in mice would prevent liver injury. 2) TLR4 antagonist in ALF prolongs survival. 3) TLR4 KO are protected from the liver injury induced by acetaminophen (APAP). Method: Study 1: 3 groups of CD1 mice were studied (n = 6 in each group) Naive, APAP, 500 mg/kg single dose IP after overnight fasting). APAP+TLR4 antagonist (STM28, OsakauniversityJapan); 20ug IP, 1 hour prior to administration of APAP and 6 hours later). Study 2: 3 groups of C57BL/6 mice were studied (n = 6) in each group. Naive, APAP (500 mg/kg single dose IP), APAP+TLR4 antagonist (IAXO (Innaxon) 3 mg/kg, 1 hour prior to administration of APAP and 6 hours later). Study 3: C57BL/6 TLR4 KO were administered APAP 500 mg/Kg and the respective Naive controls were administered saline. Biochemistry was measured using COBAS integra, Cytokines in plasma and tissue homogenate of liver, kidney and brain were measured using ELISA bead array. Brain water was measured using the dry-wet weight method. Results: Both the TLR4 antagonist’s (STM28 and IAXO compound) reduced the plasma liver enzymes, ammonia and creatinine to the control level. The increase in the plasma TNF-a induced
Journal of Hepatology 2012 vol. 56 | S21–S44
S39
ORAL PRESENTATIONS by APAP (45±3.2) was attenuated following TLR4 antagonist (20±2.3) (p < 0.01). This was associated with a reduction in brain water (p < 0.01). Both the TLR4 antagonists significantly reduced pericentral necrosis of the liver. Both these interventions showed an improvement in the survival as using the log rank test (p < 0.02). TLR4 KO mice treated with APAP were protected from liver necrosis and had significantly better survival than wild type controls (p < 0.002). Conclusion: These data provides evidence for an important of TLR4 in APAP induced ALF and provide the rationale for a clinical trial of this strategy in ALF. 92 THE HEPATIC INFLAMMATORY MICROENVIRONMENT INDUCES ENDOTOXIN TOLERANT MONOCYTES IN ACETAMINOPHEN-INDUCED LIVER FAILURE C.G. Antoniades1,2 , V. Zingarelli2 , L. Possamai1 , R. Mitry2 , W. Bernal2 , G. Auzinger2 , N. Heaton2 , A. Quaglia2 , Y. Ma2 , D. Vergani2 , J. Wendon2 , M. Thursz1 . 1 Section of Hepatology, Imperial College London, 2 Institute of Liver Studies, King’s College London, London, UK E-mail: [email protected] Background: Endotoxin-tolerant monocytes (ET), typified by reduced monocyte HLA-DR expression and attenuated proinflammatory responses, are described in human acetaminopheninduced liver failure (AALF) and may be induced by antiinflammatory mediators (e.g. IL-10, secretory leucocyte protease inhibitor [SLPI]) through toll-like receptor-4 (TLR-4) and STAT-3 signalling pathways. In AALF, the inflamed liver is characterised by elevations in anti-inflammatory/tissue repair cytokines. Aims: Using ex-vivo and in-vitro cell culture systems, we sought to investigate the effects of the hepatic inflammatory microenvironment on monocyte/macrophage function. Methods: Using Phosphoflow, ex-vivo monocyte NF-kBp65 and STAT-3 signalling was assessed in 10 AALF patients and 10 healthy controls (HC). Trans-hepatic (portal vein [PV]), hepatic vein [HV])) serum TNF-a, IL-10, SLPI (n = 5) were measured at time of transplantation. Serum (AALF [n = 34]; HC [n = 15]) and hepatic (AALF [n = 7]; HC [n = 8]) levels of TNF-a, IL-10 and SLPI were measured (pg/ml). Monocyte phenotype/function was assessed by in purified CD14+ monocytes from HC in five different tissue homogenates derived from AALF, normal liver tissue (NL) and in culture medium (CM) following 48 hours. Results: Following TLR-4 stimulation, AALF patients had reduced NF-kBp65 ratio of activation (0.8 vs 1.6; p = 0.001) and higher STAT-3 MFI compared to HC (600 vs 232; p = 0.02). AALF patients had significantly higher concentrations of IL-10 (serum: 170 vs 40; hepatic: 2 vs 0.6; p < 0.02), SLPI (serum: 71200 vs 43310; hepatic: 442 vs 116; p < 0.001) compared to HC. A transhepatic (HV>PV) gradient was seen for IL-10 and SLPI but not for TNF-a (Figure 1). In vitro, exposure to AALF homogenate induced an antiinflammatory, CD36highHLA-DRlow CD14+CD16+ macrophage phenotype (78.5% vs 63%; p = 0.03) (representative cell culture experiment shown in Figure 2).
Figure 1. Transhepatic levels of IL-10 and SLPI in acetaminophen-induced ALF patients. S40
Figure 2. Representative cell culture experiment demonstrating in vitro effects of AALF microenvironment on CD14+ monocytes.
Conclusion: In AALF, circulating monocytes show modulations in intracellular signalling pathways compatible with ET. Our data indicate that the hepatic microenvironment and production of anti-inflammatory mediators could be pivotal mediators of ET and increase the risk of infection in AALF.
Parallel Session: NASH AND ASH
93 INTERLEUKIN-10 RELEASED BY M2 KUPFFER CELLS PROMOTES M1 KUPFFER CELL APOPTOSIS: A NOVEL PROTECTIVE MECHANISM AGAINST ALCOHOLIC LIVER DISEASE J. Wan1 , M. Benkdane1 , F. Teixeira-Clerc1 , V. Deveaux1 , A. Louvet1 , F. Lafdil1 , F. Pecker1 , A. Mallat1,2 , S. Lotersztajn1 , C. Pavoine1 . 1 INSERM U955 e´quipe 17, Hˆ opital Henri-Mondor, Universit´e Paris-Est Cr´eteil, 2 Department of Hepatology and Gastroenterology, AP-HP, Groupe Henri Mondor-Albert Chenevier, Cr´eteil, France E-mail: [email protected] Aims: Activation of Kupffer cells towards a pro-inflammatory (M1) phenotype is a critical step in the deleterious process initiating alcohol-induced liver injury. We investigated whether favoring antiinflammatory (M2) polarization of Kupffer cells may protect against alcoholic liver disease. Methods: C57 Bl6/J mice were compared to BALB/c Th2-prone mice in a model of chronic alcohol exposure in which Kupffer cells are activated in the absence of inflammatory cell recruitment. M1 and M2 signature was characterized by RT-PCR; M1 and M2-polarized Kupffer cells were identified by iNOS/F4–80 (M1) or CD206/F4–80 (M2) immunohistochemistry or FACS analysis. Apoptosis was evaluated by cleaved caspase-3 labelling. In vitro studies were performed on isolated Kupffer cells, polarized into M1 and M2 by LPS or IL4. Results: in contrast to C57BL6/J mice, BALB/c mice were protected against alcohol-induced liver injury and steatosis. In response to chronic alcohol exposure, Kupffer cells from BALB/c mice displayed a preponderant M2 phenotype whereas Kupffer cells from C57BL6/J mice adopted M1 polarization. Interestingly, predominant M2 polarization was associated with selective apoptosis of M1 Kupffer cells in BALB/c livers. Studies in isolated Kupffer cells demonstrated that exposure of M1 cells to M2 conditioned medium increased cleaved caspase 3 staining of M1 Kupffer cells. Mechanistically, in vivo and in vitro data highlighted the central role of interleukin10 in M2-induced M1 apoptosis. Thus, exposure of M1 polarized macrophages to IL10 triggered their apoptosis. Moreover, anti-IL10 antibodies blunted apoptosis of M1-polarized macrophages elicited by M2 conditioned medium. In keeping with in vitro results, IL10 levels were increased in the livers of alcohol-fed BALB/c mice, as compared to C57BL6/J counterparts. Strikingly, in vivo neutralization of IL10 prevented M1 Kupffer cell apoptosis.
Journal of Hepatology 2012 vol. 56 | S21–S44