Correspondence
Hermann E. Wasmuth, Medical Department III, University Hospital Aachen (UKA), RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany
Tel: +49 241 8080861
Fax: +49 241 8082455
e-mail: [email protected] or [email protected]

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Abstract

Background: Chemokines are chemotactic mediators that are implicated in liver diseases. In viral hepatitis and primary biliary cirrhosis, a predominant chemokine receptor expressed in the liver is CXCR3, suggesting that its specific ligands are important in the progression of chronic liver diseases across different aetiologies.

Methodology/Principal findings: We analysed the serum concentrations of the CXCR3 ligands, CXCL9 (monokine induced by interferon-γ), CXCL10 (interferon-γ-inducible protein 10) and CXCL11 (interferon-inducible T cell α chemo-attractant) in healthy controls (n=53), subjects with histologically determined liver fibrosis (n=109) and patients with different stages of cirrhosis (n=153) of various disease aetiologies. Chemokine concentrations were determined by cytometric bead assay or ELISA respectively. Serum concentrations of all three chemokines were significantly increased in patients with chronic liver diseases compared with healthy controls (P<0.001). In the biopsied fibrosis cohort, CXCL9 and CXCL10 were positively associated with the severity of liver fibrosis (histology and serum markers), while CXCL11 was not. In cirrhotic patients, CXCL9 was increased in early Child–Pugh stages, while CXCL11 was elevated only in Child B and C patients and CXCL10 across all stages. Notably, CXCR3 chemokines were also associated with the development of clinical complications of cirrhosis, especially portal hypertension. All chemokines significantly correlated with serum levels of the hepatoprotective cytokines interleukin (IL)-6 and IL-10, suggesting their involvement in a counter-regulatory response during the progression of liver disease, shedding new light on their involvement in the pathophysiology of chronic liver diseases.

Conclusions: CXCR3 chemokines are differentially expressed during chronic liver diseases across different disease stages and aetiologies. Their association with portal hypertension and hepatoprotective cytokines implies biological functions beyond immune cell recruitment, thereby provoking new diagnostic and therapeutic concepts.

References

1 Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008; 371: 838–51.
10.1016/S0140-6736(08)60383-9
CAS PubMed Web of Science® Google Scholar
2 Durand F, Valla D. Assessment of prognosis of cirrhosis. Semin Liver Dis 2008; 28: 110–22.
10.1055/s-2008-1040325
CAS PubMed Web of Science® Google Scholar
3 Huo TI, Lee SD, Lin HC. Selecting an optimal prognostic system for liver cirrhosis: the model for end-stage liver disease and beyond. Liver Int 2008; 28: 606–13.
PubMed Web of Science® Google Scholar
4 Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134: 1655–69.
10.1053/j.gastro.2008.03.003
CAS PubMed Web of Science® Google Scholar
5 Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 2009; 51: 371–9.
10.1016/j.jhep.2009.03.019
CAS PubMed Web of Science® Google Scholar
6 Asselah T, Bieche I, Laurendeau I, et al. Liver gene expression signature of mild fibrosis in patients with chronic hepatitis C. Gastroenterology 2005; 129: 2064–75.
10.1053/j.gastro.2005.09.010
CAS PubMed Web of Science® Google Scholar
7 Wasmuth HE, Tacke F, Trautwein C. Chemokines in liver inflammation and fibrosis. Semin Liver Dis 2010; 30: 215–25.
10.1055/s-0030-1255351
CAS PubMed Web of Science® Google Scholar
8 Holt AP, Salmon M, Buckley CD, Adams DH. Immune interactions in hepatic fibrosis. Clin Liver Dis 2008; 12: 861–82, x.
10.1016/j.cld.2008.07.002
PubMed Web of Science® Google Scholar
9 Karlmark KR, Wasmuth HE, Trautwein C, Tacke F. Chemokine-directed immune cell infiltration in acute and chronic liver disease. Expert Rev Gastroenterol Hepatol 2008; 2: 233–42.
10.1586/17474124.2.2.233
CAS PubMed Google Scholar
10 Shields PL, Morland CM, Salmon M, et al. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 1999; 163: 6236–43.
10.4049/jimmunol.163.11.6236
CAS PubMed Web of Science® Google Scholar
11 Chuang YH, Lian ZX, Cheng CM, et al. Increased levels of chemokine receptor CXCR3 and chemokines IP-10 and MIG in patients with primary biliary cirrhosis and their first degree relatives. J Autoimmun 2005; 25: 126–32.
10.1016/j.jaut.2005.08.009
CAS PubMed Web of Science® Google Scholar
12 Lasagni L, Francalanci M, Annunziato F, et al. An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. J Exp Med 2003; 197: 1537–49.
10.1084/jem.20021897
CAS PubMed Web of Science® Google Scholar
13 Dominguez M, Miquel R, Colmenero J, et al. Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis. Gastroenterology 2009; 136: 1639–50.
10.1053/j.gastro.2009.01.056
CAS PubMed Web of Science® Google Scholar
14 Zaldivar MM, Pauels K, Von Hundelshausen P, et al. The CXC chemokine ligand 4 (CXCL4) is a platelet-derived mediator of experimental liver fibrosis. Hepatology 2010; 51: 1345–53.
10.1002/hep.23435
CAS PubMed Web of Science® Google Scholar
15 Zeremski M, Dimova R, Brown Q, et al. Peripheral CXCR3-associated chemokines as biomarkers of fibrosis in chronic hepatitis C virus infection. J Infect Dis 2009; 200: 1774–80.
10.1086/646614
CAS PubMed Web of Science® Google Scholar
16 Wasmuth HE, Lammert F, Zaldivar MM, et al. Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans. Gastroenterology 2009; 137: 309–19. e1–3.
10.1053/j.gastro.2009.03.053
CAS PubMed Web of Science® Google Scholar
17 Roe B, Coughlan S, Hassan J, et al. Elevated serum levels of interferon-gamma-inducible protein-10 in patients coinfected with hepatitis C virus and HIV. J Infect Dis 2007; 196: 1053–7.
10.1086/520935
CAS PubMed Web of Science® Google Scholar
18 Berres ML, Trautwein C, Schmeding M, et al. Serum chemokine CXC ligand 10 (CXCL10) predicts fibrosis progression after liver transplantation for hepatitis C infection. Hepatology 2011; 53: 596–603.
10.1002/hep.24098
CAS PubMed Web of Science® Google Scholar
19 Zeremski M, Petrovic LM, Chiriboga L, et al. Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C. Hepatology 2008; 48: 1440–50.
10.1002/hep.22500
CAS PubMed Web of Science® Google Scholar
20 Harvey CE, Post JJ, Palladinetti P, et al. Expression of the chemokine IP-10 (CXCL10) by hepatocytes in chronic hepatitis C virus infection correlates with histological severity and lobular inflammation. J Leukoc Biol 2003; 74: 360–9.
10.1189/jlb.0303093
CAS PubMed Web of Science® Google Scholar
21 Santodomingo-Garzon T, Han J, Le T, Yang Y, Swain MG. Natural killer T cells regulate the homing of chemokine CXC receptor 3-positive regulatory T cells to the liver in mice. Hepatology 2009; 49: 1267–76.
10.1002/hep.22761
CAS PubMed Web of Science® Google Scholar
22 Casrouge A, Decalf J, Ahloulay M, et al. Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV. J Clin Invest 2011; 121: 308–17.
10.1172/JCI40594
CAS PubMed Web of Science® Google Scholar
23 Pockros PJ, Jeffers L, Afdhal N, et al. Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-gamma1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis. Hepatology 2007; 45: 569–78.
10.1002/hep.21561
CAS PubMed Web of Science® Google Scholar
24 Zimmermann HW, Seidler S, Nattermann J, et al. Functional contribution of elevated circulating and hepatic non-classical CD14+CD16+monocytes to inflammation and human liver fibrosis. PLoS One 2010; 5: e11049.
10.1371/journal.pone.0011049
CAS PubMed Web of Science® Google Scholar
25 Wasmuth HE, Kunz D, Yagmur E, et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol 2005; 42: 195–201.
10.1016/j.jhep.2004.10.019
CAS PubMed Web of Science® Google Scholar
26 Yagmur E, Rizk M, Stanzel S, et al. Elevation of endoglin (CD105) concentrations in serum of patients with liver cirrhosis and carcinoma. Eur J Gastroenterol Hepatol 2007; 19: 755–61.
10.1097/MEG.0b013e3282202bea
CAS PubMed Web of Science® Google Scholar
27 Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994; 19: 1513–20.
CAS PubMed Web of Science® Google Scholar
28 Karlmark KR, Weiskirchen R, Zimmermann HW, et al. Hepatic recruitment of the inflammatory Gr1+monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 2009; 50: 261–74.
10.1002/hep.22950
CAS PubMed Web of Science® Google Scholar
29 Yagmur E, Weiskirchen R, Gressner AM, Trautwein C, Tacke F. Insulin resistance in liver cirrhosis is not associated with circulating retinol-binding protein 4. Diabetes Care 2007; 30: 1168–72.
10.2337/dc06-2323
CAS PubMed Web of Science® Google Scholar
30 Tacke F, Fiedler K, Trautwein C. A simple clinical score predicts high risk for upper gastrointestinal hemorrhages from varices in patients with chronic liver disease. Scand J Gastroenterol 2007; 42: 374–82.
10.1080/00365520600930826
PubMed Web of Science® Google Scholar
31 Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008; 134: 1670–81.
10.1053/j.gastro.2008.03.001
CAS PubMed Web of Science® Google Scholar
32 Streetz KL, Tacke F, Leifeld L, et al. Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases. Hepatology 2003; 38: 218–29.
10.1053/jhep.2003.50268
CAS PubMed Web of Science® Google Scholar
33 Rockey DC. Current and future anti-fibrotic therapies for chronic liver disease. Clin Liver Dis 2008; 12: 939–62, xi.
10.1016/j.cld.2008.07.011
PubMed Web of Science® Google Scholar
34 Helbig KJ, Ruszkiewicz A, Lanford RE, et al. Differential expression of the CXCR3 ligands in chronic hepatitis C virus (HCV) infection and their modulation by HCV in vitro. J Virol 2009; 83: 836–46.
10.1128/JVI.01388-08
CAS PubMed Web of Science® Google Scholar
35 Curbishley SM, Eksteen B, Gladue RP, Lalor P, Adams DH. CXCR 3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow. Am J Pathol 2005; 167: 887–99.
10.1016/S0002-9440(10)62060-3
CAS PubMed Web of Science® Google Scholar
36 Schrage A, Wechsung K, Neumann K, et al. Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines. Hepatology 2008; 48: 1262–72.
10.1002/hep.22443
CAS PubMed Web of Science® Google Scholar
37 Holt AP, Haughton EL, Lalor PF, et al. Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver. Gastroenterology 2009; 136: 705–14.
10.1053/j.gastro.2008.10.020
CAS PubMed Web of Science® Google Scholar
38 Oo YH, Weston CJ, Lalor PF, et al. Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J Immunol 2010; 184: 2886–98.
10.4049/jimmunol.0901216
CAS PubMed Web of Science® Google Scholar
39 Perney P, Turriere C, Portales P, et al. CXCR3 expression on peripheral CD4+T cells as a predictive marker of response to treatment in chronic hepatitis C. Clin Immunol 2009; 132: 55–62.
10.1016/j.clim.2009.03.521
CAS PubMed Web of Science® Google Scholar
40 Mizuochi T, Ito M, Saito K, et al. Possible recruitment of peripheral blood CXCR3+CD27+CD19+B cells to the liver of chronic hepatitis C patients. J Interferon Cytokine Res 2010; 30: 243–52.
10.1089/jir.2009.0047
CAS PubMed Web of Science® Google Scholar
41 Hintermann E, Bayer M, Pfeilschifter JM, Luster AD, Christen U. CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation. J Autoimmun 2010; 35: 424–35.
10.1016/j.jaut.2010.09.003
CAS PubMed Web of Science® Google Scholar
42 Standish RA, Cholongitas E, Dhillon A, Burroughs AK, Dhillon AP. An appraisal of the histopathological assessment of liver fibrosis. Gut 2006; 55: 569–78.
10.1136/gut.2005.084475
CAS PubMed Web of Science® Google Scholar
43 Goodman ZD, Stoddard AM, Bonkovsky HL, et al. Fibrosis progression in chronic hepatitis C: morphometric image analysis in the HALT-C trial. Hepatology 2009; 50: 1738–49.
Web of Science® Google Scholar
44 Mackay CR. Chemokines: immunology's high impact factors. Nat Immunol 2001; 2: 95–101.
CAS PubMed Web of Science® Google Scholar
45 Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006; 354: 610–21.
10.1056/NEJMra052723
CAS PubMed Web of Science® Google Scholar
46 Fernandez M, Semela D, Bruix J, et al. Angiogenesis in liver disease. J Hepatol 2009; 50: 604–20.
10.1016/j.jhep.2008.12.011
CAS PubMed Web of Science® Google Scholar
47 Feldman ED, Weinreich DM, Carroll NM, et al. Interferon gamma-inducible protein 10 selectively inhibits proliferation and induces apoptosis in endothelial cells. Ann Surg Oncol 2006; 13: 125–33.
10.1245/ASO.2006.03.038
PubMed Web of Science® Google Scholar
48 Strieter RM, Belperio JA, Burdick MD, Keane MP. CXC chemokines in angiogenesis relevant to chronic fibroproliferation. Curr Drug Targets Inflamm Allergy 2005; 4: 23–6.
10.2174/1568010053622902
CAS PubMed Google Scholar

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Volume31, Issue6

July 2011

Pages 840-849

Serum chemokine receptor CXCR3 ligands are associated with progression, organ dysfunction and complications of chronic liver diseases

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Serum chemokine receptor CXCR3 ligands are associated with progression, organ dysfunction and complications of chronic liver diseases

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