Hepatitis C Virus (HCV)-Induced Inflammation: The Role of Cross-Talk Between HCV-Infected Hepatocytes and Stellate Cells

Fig. 9.1

Cross-talk between hepatitis C virus (HCV)-infected hepatocytes and hepatic stellate cells (HSCs) induces macrophage inflammatory protein (MIP)-1β expression. (a) Hepatocytes or HCV-infected hepatocytes were cultured alone or in the presence of HSCs for 24 h. The expression of MIP-1β was measured by quantitative real-time polymerase chain reaction (qRT-PCR). (b) Hepatocytes or HCV-infected hepatocytes were treated with conditioned medium from hepatocytes (Hepatocyte-CM) or HSCs (HSC-CM) for 24 h. The expression of MIP-1β was measured by qRT-PCR. (c) HSCs were treated with transforming growth factor (TGF)-β1 for 24 h. Hepatocytes or HCV-infected hepatocytes were treated with HSC-CM or TGF-β1-stimulated HCS-CM for 24 h. The expression of MIP-1β was measured by qRT-PCR

Fig. 9.2

Interleukin (IL)-1α and CCAAT (cytosine–cytosine–adenosine–adenosine–thymidine)-enhancer-binding protein (C/EBP)-β contribute to the hepatitis C virus (HCV)-infected hepatocyte response to hepatic stellate cells (HSCs). (a) HCV-infected hepatocytes were cultured with HSCs together with an isotype control, anti-IL-1, or IL-1 receptor antagonist (IL-1RA) for 24 h. Macrophage inflammatory protein (MIP)-1 expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). (b) Hepatocytes or HCV-infected hepatocytes were treated with various amounts of recombinant IL-1 (0, 0.1, 1.0, 10, or 100 pg/ml) for 24 h. MIP-1 expression was analyzed by qRT-PCR. (c) Hepatocytes and HCV-infected hepatocytes were transfected with control small-interfering RNA (siRNA) or small-interfering C/EBP (siC/EBP)-β. After 24 h of transfection, the cells were treated with conditioned medium from hepatocytes (Hepatocyte-CM) or HSCs (HSC-CM) for 24 h. MIP-1 expression was analyzed by qRT-PCR

These results suggest that TGF-β, which is induced by HCV infection, stimulates quiescent HSCs, and activation or trans-differentiation of HSCs leads to the expression of IL-1α, resulting in increased levels of inflammatory cytokines and chemokines in HCV-infected hepatocytes (Fig. 9.3).

Fig. 9.3

Cross-talk between hepatitis C virus (HCV)-infected hepatocytes and hepatic stellate cells (HSCs). (a) HCV infection induces the expression of growth factors, such as transforming growth factor (TGF)-β. (b) When quiescent HSCs are activated by growth factors, activated HSCs secrete inflammatory cytokines, such as interleukin (IL)-1α. (c) HCV-infected cells are stimulated by IL-1α. An increase in inflammatory cytokine production accelerates inflammation in the liver

References

Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545CrossRefPubMed

Becker C et al (2005) IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle 4:217–220CrossRefPubMed

Brun P et al (2005) Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 289:571–578CrossRef

Burdette D et al (2012) Hepatitis C virus activates interleukin-1β via caspase-1-inflammasome complex. J Gen Virol 93:235–246CrossRefPubMedCentralPubMed

Chackerian AA et al (2007) IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. J Immunol 179:2551–2555CrossRefPubMed

Chang ML et al (2007a) Topological and evolutional relationships between HCV core protein and hepatic lipid vesicles: studies in vitro and in conditionally transgenic mice. World J Gastroenterol 13:3472–3477CrossRefPubMedCentralPubMed

Chang S et al (2007b) Toll-like receptors 1 and 6 are involved in TLR2-mediated macrophage activation by hepatitis C virus core and NS3 proteins. J Leukoc Biol 82:479–487CrossRefPubMed

Chang ML et al (2008) Acute expression of hepatitis C core protein in adult mouse liver: mitochondrial stress and apoptosis. Scand J Gastroenterol 43:747–755CrossRefPubMed

Chang ML et al (2009) Hepatic inflammation mediated by hepatitis C virus core protein is ameliorated by blocking complement activation. BMC Med Genomics 2:51CrossRefPubMedCentralPubMed

Chen W et al (2014) HCV genomic RNA activates the NLRP3 inflammasome in human myeloid cells. PLoS One 9:e84953CrossRefPubMedCentralPubMed

Chou AH et al (2005) Hepatitis C virus core protein modulates TRAIL-mediated apoptosis by enhancing Bid cleavage and activation of mitochondria apoptosis signaling pathway. J Immunol 174:2160–2166CrossRefPubMed

Clément S et al (2010) The hepatitis C virus core protein indirectly induces alpha-smooth muscle actin expression in hepatic stellate cells via interleukin-8. J Hepatol 52:635–643CrossRefPubMed

Corpechot C et al (2002) Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 35:1010–1021CrossRefPubMed

Coulouarn C et al (2012) Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma. Cancer Res 72:2533–2542CrossRefPubMedCentralPubMed

Dolganiuc A et al (2003) Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation. J Immunol 170:5615–5624CrossRefPubMed

Dolganiuc A et al (2004) Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. Gastroenterology 127:1513–1524CrossRefPubMed

Duffield JS et al (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115:56–65CrossRefPubMedCentralPubMed

Friedman SL (2008a) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88:125–172CrossRefPubMedCentralPubMed

Friedman SL (2008b) Mechanisms of hepatic fibrogenesis. Gastroenterology 2008(134):1655–1669CrossRef

Harvey CE et al (2003) 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 74:360–369CrossRefPubMed

Hernandez-Gea V, Friedman SL (2011) Pathogenesis of liver fibrosis. Annu Rev Pathol 6:425–456CrossRefPubMed

Hosomura N et al (2011) HCV-related proteins activate Kupffer cells isolated from human liver tissues. Dig Dis Sci 56:1057–1064CrossRefPubMed

Hou FF et al (2000) Phenotypic and functional characteristics of macrophage-like cells differentiated in pro-inflammatory cytokine-containing cultures. Immunol Cell Biol 78:205–213CrossRefPubMed

Idéo G et al (1999) Antioxidant drugs combined with alpha-interferon in chronic hepatitis C not responsive to alpha-interferon alone: a randomized, multicentre study. Eur J Gastroenterol Hepatol 11:1203–1207CrossRefPubMed

Isse K et al (2005) Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts. Hepatology 41:506–516CrossRefPubMed

Jing Y et al (2011) Tumor necrosis factor-alpha promotes tumor growth by inducing vascular endothelial growth factor. Cancer Invest 29:485–493PubMed

Only gold members can continue reading. Log In or Register to continue