The relationship between expression of Toll-like Receptor 4 in chronic hepatitis C patients and different stages of liver fibrosis

Salem Youssef Mohamed, Ehab Fawzy Mostafa, Amr Shaaban Hanafy, Hesham Atia, Ashraf Metwally, Ayman M. Marei

Abstract


1221

Background and Aims

Toll-like Receptor 4(TLR4) is a pattern recognition receptor whose activation results in the production of several pro-inflammatory cytokines. The objective of this work is to find if there is a relation between the expression of TLR4 and fibrosis progression in chronic HCV patients.

Methods

Fifty patients with chronic HCV were included. They were divided into group A: 40 patients (F1-F4) and group B (control group) which included ten patients (F0) based on fibroscan value. All patients were exposed to clinical and laboratory evaluations preliminary to antiviral therapy, assessment of TLR4 mRNA by Real Time- PCR.

Results

Twenty-eight males and 22 females with a mean age 28.9±6.1 years. The mean TLR4 expression is 11.2±7.4 folds, TLR4 expression in F0 group is 2.8±1.9, in F1 group 4.8±1.5, F2 group 10.2±2.5, F3 group 16.8±1.5 and in F4 21.3±3.6 folds (p<0.001). TLR4 showed a positive correlation with age, fibrosis stage, HCV RNA, serum transaminases, total bilirubin and prothrombin time, a negative correlation with platelet count and serum albumin. Fibrosis progression was independently associated with TLR4 expression (?=0. 648, P=0. 000), RNA (?= 0.160, P =0.001) and platelet count (?= -0.248, P = 0.004).

Conclusion

The expression of TLR4 is highly correlated with the fibrosis progression; TLR4 may be a potential target for drugs to limit the progression of fibrosis.

Keywords: Toll-like Receptor 4, chronic HCV patients, liver fibrosis, fibroscan, HCV RNA


Keywords


Toll-like Receptor 4, chronic hepatitis C, fibroscan,liver cirrhosis

References


Friedman S L. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134 (6):1655–1669

Bosetti C, Levi F, Zatonski WA, Negri E, LaVecchia C. Worldwide mortality from cirrhosis: An update to 2002. J.Hepatology 2007; 46(5), 827-839.

Friedman SL. Liver fibrosis from bench to bedside. J Hepatol 2003; 38 (1):S38-S53.

De Torres M, Poynard M. Risk factors for liver fibrosis progression in patients with chronic hepatitis C. Annals of hepatology 2003;2(1):5-11.

Borrello S, Nicolò C, Delogu G, Pandolfi F, Ria F. TLR2: crossroads between infections and autoimmunity. International journal of immunopathology and pharmacology 2011; 24 (3): 549–556.

Pimentel-Nunes P, Soares JB, Roncon-Albuquerque R, Dinis- Ribeiro M, Leite-Moreira AF. Toll-like receptors as therapeutic targets in gastrointestinal diseases. Expert Opin Ther Targets 2010; 14:347–368.

Re F, Strominger JL. Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness. J Biol Chem 2002; 277(26): 23427–23432.

Chuang TH, Ulevitch RJ. Triad 3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors. Nat Immunol 2004;5(5):495–502.

Zhang G, Ghosh S. Negative regulation of toll-like receptor-mediated signaling by Tollip. J Biol Chem 2002; 277(9):7059-7065.

Husebye H, Aune MH, Stenvik J, Samstad E, Skjeldal F, Halaas O, et al. The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes. Immunity 2010;33(4):583–596.

Seki E, Tsutsui H, Nakano H, Tsuji N, Hoshino K, Adachi O, et al. Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in the induction of production of IL-12 and IL-1beta. J Immunol 2001; 166:2651–2657.

Paik Y, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA.Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 2003; 37:1043–1055.

Dolganiuc A, Norkina O, Kodys K, Catalano D, Bakis G, Marshall C, et al. Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection. Gastroenterology2007; 133:1627–1636.

Wi SM, Moon G, Kim J, Kim ST, Shim JH, Chun E, Lee KY. TAK1-ECSIT-TRAF6 complex plays a key role in the TLR4 signal to activate NF-κB. J Biol Chem 2014; 289(51):35205-14.

Machida K, Tsukamoto H, Mkrtchyan H, Duan L, Dynnyk A, Liu HM, et al. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc Natl Acad Sci USA 2009; 106:1548–1553.

Giannini EG, Botta F, Borro P, Dulbecco P, Testa E, Mansi C, et al. Application of the platelet count/spleen diameter ratio to rule out the presence of oesophageal varices in patients with cirrhosis: A validation study based on follow-up. Digestive and Liver Disease 2005; 37(10): 779-785.

Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008; 48(5):835-847.

Andreakos E, Foxwell B, Feldmann M. Is targeting toll-like receptors and their signaling pathway a useful therapeutic approach to modulating cytokine-driven inflammation? Immunol Rev 2004; 202:250–265.

Bataller R, Brenner DA. Liver fibrosis. Journal of Clinical Investigation 2005; 115(2):209–218.

Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007;13(11):1324-1332.

Machida K, Cheng KTH, Sung VM, Levine AM, Foung S, Lai MMC. Hepatitis C virus induces toll-like receptor 4 expression, leading to enhanced production of beta interferon and interleukin-6. J Virol 2006; 80:866–874.

Fanning L, Kenny E, Sheehan M, Cannon B, Whelton M, O'Connell J et al. Viral load and clinicopathological features of chronic hepatitis C (1b) in a homogeneous patient population. Hepatology 1999; 29(3): 903-907.

Vespasiani-Gentilucci U, Carotti S, Onetti-Muda A, Perrone G, Ginanni-Corradini S, Latasa MU, et al. Toll-like receptor-4 expression by hepatic progenitor cells and biliary epithelial cells in HCV-related chronic liver disease. Modern Pathology 2012; 25: 576–589.

Guo J, Loke J, Zheng F, Hong F, Yea S, Fukata M et al. Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology 2009; 49:960-968.




DOI: http://dx.doi.org/10.22037/ghfbb.v0i0.1079

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GHFBB by Gastroenterology and Liver Diseases Research Institute is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

 

PISSN: 2008-2258

EISSN: 2008-4234


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