Protein S exacerbates alcoholic hepatitis by stimulating liver natural killer T cells

被引：15

作者：

Chelakkot-Govindalayathil, A. -L. ^{[1
]}

Mifuji-Moroka, R. ^{[2
]}

D'Alessandro-Gabazza, C. N. ^{[1
]}

Toda, M. ^{[1
]}

Matsuda, Y. ^{[3
]}

Gil-Bernabe, P. ^{[1
]}

Roeen, Z. ^{[1
]}

Yasuma, T. ^{[4
]}

Yano, Y. ^{[4
]}

Gabazza, E. C. ^{[1
]}

Iwasa, M. ^{[2
]}

Takei, Y. ^{[2
]}

机构：

[1] Mie Univ, Dept Immunol, Grad Sch Med, Tsu, Mie 5148507, Japan

[2] Mie Univ, Dept Gastroenterol & Hepatol, Sch Med, Tsu, Mie 5148507, Japan

[3] Mie Univ, Grad Sch Med, Dept Pathol & Lab Med, Tsu, Mie 5148507, Japan

[4] Mie Univ, Grad Sch Med, Dept Diabet Metab & Endocrinol, Tsu, Mie 5148507, Japan

来源：

JOURNAL OF THROMBOSIS AND HAEMOSTASIS | 2015年 / 13卷 / 01期

关键词：

alcoholism; anticoagulants; hepatitis; natural killer T cells; protein S; INNATE IMMUNE-RESPONSE; OXIDATIVE STRESS; NKT CELLS; DISEASE; ETHANOL; INJURY; MICE; APOPTOSIS; HEPATOCYTES; ACTIVATION;

D O I：

10.1111/jth.12789

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BackgroundAlcohol consumption is a major cause of liver injury but the mechanisms are not completely understood. Protein S (PS) is an anticoagulant glycoprotein with multiple functions. The role of PS in liver injury is unknown. ObjectivesThis study investigated the role of PS in acute alcoholic hepatitis. MethodsA mouse overexpressing human PS (hPS-TG) was generated in which acute hepatitis was induced by intraperitoneal injection of ethanol. ResultsThe levels of serum liver enzymes and liver tissue inflammatory cytokines and the degree of hepatic steatosis were significantly increased in hPS-TG mice treated with ethanol compared with ethanol-treated wild type (WT) mice. Cell expansion, activation and inhibition of apoptosis were significantly augmented in natural killer T (NKT) cells from hPS-TG mice compared with WT mice. Liver mononuclear cells from hPS-TG mice express higher levels of inflammatory cytokines than those from WT mice after stimulation with a specific stimulant of NKT cells in vitro. In a co-culture system of hepatocytes and NKT cells, the effects of PS on ethanol-mediated cell injury were suppressed by a CD1d neutralizing antibody. Alcoholic liver injury was significantly improved in mice pre-treated with PS siRNA and anti-protein S antibody compared with control mice. Patients with alcoholic hepatitis showed significantly increased plasma PS levels and enhanced liver expression of PS and CD1d compared with controls. ConclusionsThe results of this study suggest that PS exacerbates acute alcoholic hepatitis by inhibiting apoptosis of activated NKT cells.

引用

页码：142 / 154

页数：13

共 46 条

[1] Natural anticoagulants can be useful predictors of severity in chronic liver disease [J].

Abdo, Ayman A. ;

Sanai, Faisal M. ;

Azzam, Nahla ;

Al Sawat, Khalid ;

Dukhayil, Manal Ai ;

Al Ghumlas, Abeer ;

Hersi, Ahmad ;

Gader, Abdel Galil Abdel .

BLOOD COAGULATION & FIBRINOLYSIS, 2010, 21 (02) :122-127

[2] Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells [J].

Anderson, HA ;

Maylock, CA ;

Williams, JA ;

Paweletz, CP ;

Shu, HJ ;

Shacter, E .

NATURE IMMUNOLOGY, 2003, 4 (01) :87-91

[3] Oxidants and antioxidants in alcohol-induced liver disease [J].

Arteel, GE .

GASTROENTEROLOGY, 2003, 124 (03) :778-790

[4] High incidence of tumors in diabetic thrombin activatable fibrinolysis inhibitor and apolipoprotein E double-deficient mice [J].

Beppu, T. ;

Gil-Bernabe, P. ;

Boveda-Ruiz, D. ;

D'Alessandro-Gabazza, C. ;

Matsuda, Y. ;

Toda, M. ;

Miyake, Y. ;

Shiraki, K. ;

Murata, M. ;

Murata, T. ;

Yano, Y. ;

Morser, J. ;

Gabazza, E. C. ;

Takei, Y. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2010, 8 (11) :2514-2522

[5] The innate immune response during liver inflammation and metabolic disease [J].

Bieghs, Veerie ;

Trautwein, Christian .

TRENDS IN IMMUNOLOGY, 2013, 34 (09) :446-452

[6] Lack of Protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis [J].

Burstyn-Cohen, Tal ;

Heeb, Mary Jo ;

Lemke, Greg .

JOURNAL OF CLINICAL INVESTIGATION, 2009, 119 (10) :2942-2953

[7] Alcohol Facilitates CD1d Loading, Subsequent Activation of NKT Cells, and Reduces the Incidence of Diabetes in NOD Mice [J].

Buschard, Karsten ;

Hansen, Axel Kornerup ;

Jensen, Karen ;

Lindenbergh-Kortleve, Dicky J. ;

de Ruiter, Lilian F. ;

Krohn, Thomas C. ;

Hufeldt, Majbritt R. ;

Vogensen, Finn K. ;

Aasted, Bent ;

Osterbye, Thomas ;

Roep, Bart O. ;

de Haar, Colin ;

Nieuwenhuis, Edward E. .

PLOS ONE, 2011, 6 (04)

[8] Acute alcoholic hepatitis [J].

Ceccanti, Mauro ;

Attili, Adolfo ;

Balducci, Giuseppe ;

Attilia, Fabio ;

Giacomelli, Stefano ;

Rotondo, Claudia ;

Sasso, Guido Francesco ;

Xirouchakis, Elias ;

Attilia, Maria Luisa .

JOURNAL OF CLINICAL GASTROENTEROLOGY, 2006, 40 (09) :833-841

[9] Determination of Cellular Lipids Bound to Human CD1d Molecules [J].

Cox, Daryl ;

Fox, Lisa ;

Tian, Runying ;

Bardet, Wilfried ;

Skaley, Matthew ;

Mojsilovic, Danijela ;

Gumperz, Jenny ;

Hildebrand, William .

PLOS ONE, 2009, 4 (05)

[10] Advances in understanding pathogenic mechanisms of thrombophilic disorders [J].

Dahlback, Bjorn .

BLOOD, 2008, 112 (01) :19-27

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