NF‑κB inhibition alleviates carbon tetrachloride‑induced liver fibrosis via suppression of activated hepatic stellate cells

Wang,Fei; Liu,Shuyuan; Du,Taiping; Chen,Hao; Li,Zhiyong; Yan,Jingwang

doi:10.3892/etm.2014.1682

NF‑κB inhibition alleviates carbon tetrachloride‑induced liver fibrosis via suppression of activated hepatic stellate cells

Authors:
- Fei Wang
- Shuyuan Liu
- Taiping Du
- Hao Chen
- Zhiyong Li
- Jingwang Yan
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Affiliations: Department of General Surgery Ward 1, Xinxiang Central Hospital, Xinxiang, Henan 453000, P.R. China, Department of Infectious Diseases, Third Affiliated Hospital of Xinxiang Medical College, Xinxiang, Henan 453000, P.R. China
Published online on: April 14, 2014 https://doi.org/10.3892/etm.2014.1682
Pages: 95-99

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Abstract

An effective treatment for hepatic fibrosis is not available clinically. Nuclear factor (NF)‑κB plays a central role in inflammation and fibrosis. The aim of the present study was to investigate the effect of an NF‑κB inhibitor, BAY‑11‑7082 (BAY), on mouse liver fibrosis. The effects of BAY on hepatic stellate cell (HSC) activation were measured in the lipopolysaccharide‑activated rat HSC‑T6 cell line. In addition, the therapeutic effect of BAY was studied in vivo using a model of hepatic fibrosis induced by carbon tetrachloride (CCl4) in mice. BAY effectively decreased the cell viability of activated HSC‑T6 cells and suppressed HSC‑T6 activation by downregulating the expression of collagen I and α‑smooth muscle actin. BAY significantly inhibited the phosphorylation of phosphatidylinositol 3‑kinase (PI3K) and serine/threonine kinase‑protein kinase B (Akt) in activated HSC‑T6 cells. In addition, administration of BAY attenuated mouse liver fibrosis induced by CCl4, as shown by histology and the expression of profibrogenic markers. BAY also significantly decreased the levels of serum alanine aminotransferase in this model of hepatic fibrosis. Therefore, the results of the present study demonstrate that BAY attenuates liver fibrosis by blocking PI3K and Akt phosphorylation in activated HSCs. Thus, BAY demonstrates therapeutic potential as a treatment for hepatic fibrosis.

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1	Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology. 134:1655–1669. 2008. View Article : Google Scholar : PubMed/NCBI
2	Jiao J, Friedman SL and Aloman C: Hepatic fibrosis. Curr Opin Gastroenterol. 25:223–229. 2009. View Article : Google Scholar
3	Bataller R and Brenner DA: Liver fibrosis. J Clin Invest. 115:209–218. 2005. View Article : Google Scholar
4	Friedman SL: Reversibility of hepatic fibrosis and cirrhosis - is it all hype? Nat Clin Pract Gastroenterol Hepatol. 4:236–237. 2007. View Article : Google Scholar : PubMed/NCBI
5	Tangkijvanich P and Yee HF Jr: Cirrhosis - can we reverse hepatic fibrosis? Eur J Surg Suppl. 587:100–112. 2002.PubMed/NCBI
6	Povero D, Busletta C, Novo E, et al: Liver fibrosis: a dynamic and potentially reversible process. Histol Histopathol. 25:1075–1091. 2010.PubMed/NCBI
7	Schuppan D and Kim YO: Evolving therapies for liver fibrosis. J Clin Invest. 123:1887–1901. 2013. View Article : Google Scholar : PubMed/NCBI
8	Gressner AM and Weiskirchen R: Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med. 10:76–99. 2006. View Article : Google Scholar : PubMed/NCBI
9	Gressner AM, Weiskirchen R, Breitkopf K and Dooley S: Roles of TGF-beta in hepatic fibrosis. Front Biosci. 7:d793–d807. 2002. View Article : Google Scholar : PubMed/NCBI
10	Gressner OA and Gressner AM: Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases. Liver Int. 28:1065–1079. 2008. View Article : Google Scholar : PubMed/NCBI
11	Robinson SM and Mann DA: Role of nuclear factor kappaB in liver health and disease. Clin Sci (Lond). 118:691–705. 2010. View Article : Google Scholar : PubMed/NCBI
12	Gao Q, Wang XY, Zhou J and Fan J: Cell line misidentification: the case of the Chang liver cell line. Hepatology. 54:1894–1895. 2011. View Article : Google Scholar : PubMed/NCBI
13	Hao ZM, Cai M, Lv YF, Huang YH and Li HH: Oral administration of recombinant adeno-associated virus-mediated bone morphogenetic protein-7 suppresses CCl(4)-induced hepatic fibrosis in mice. Mol Ther. 20:2043–2051. 2012. View Article : Google Scholar : PubMed/NCBI
14	Kar S, Ukil A and Das PK: Cystatin cures visceral leishmaniasis by NF-κB-mediated proinflammatory response through co-ordination of TLR/MyD88 signaling with p105-TpI2-ERK pathway. Eur J Immunol. 41:116–127. 2011.PubMed/NCBI
15	Zhao J, Zhang H, Huang Y, et al: Bay11–7082 attenuates murine lupus nephritis via inhibiting NLRP3 inflammasome and NF-κB activation. Int Immunopharmacol. 17:116–122. 2013.
16	Luedde T and Schwabe RF: NF-κB in the liver - linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 8:108–118. 2011.
17	Bonacchi A, Petrai I, Defranco RM, et al: The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C. Gastroenterology. 125:1060–1076. 2003.PubMed/NCBI
18	Seki E, De Minicis S, Osterreicher CH, et al: TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 13:1324–1332. 2007. View Article : Google Scholar : PubMed/NCBI
19	Seki E, De Minicis S, Gwak GY, et al: CCR1 and CCR5 promote hepatic fibrosis in mice. J Clin Invest. 119:1858–1870. 2009.PubMed/NCBI
20	Miura K, Kodama Y, Inokuchi S, et al: Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology. 139:323–334. 2010. View Article : Google Scholar : PubMed/NCBI
21	Duffield JS, Forbes SJ, Constandinou CM, et al: Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 115:56–65. 2005. View Article : Google Scholar : PubMed/NCBI
22	Son G, Iimuro Y, Seki E, Hirano T, Kaneda Y and Fujimoto J: Selective inactivation of NF-kappaB in the liver using NF-kappaB decoy suppresses CCl₄-induced liver injury and fibrosis. Am J Physiol Gastrointest Liver Physiol. 293:G631–G639. 2007. View Article : Google Scholar : PubMed/NCBI
23	Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C and Brenner DA: Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology. 37:1043–1055. 2003. View Article : Google Scholar : PubMed/NCBI
24	Hellerbrand C, Jobin C, Iimuro Y, Licato L, Sartor RB and Brenner DA: Inhibition of NFkappaB in activated rat hepatic stellate cells by proteasome inhibitors and an IkappaB super-repressor. Hepatology. 27:1285–1295. 1998. View Article : Google Scholar : PubMed/NCBI
25	Oakley F, Teoh V, Ching-A-Sue G, et al: Angiotensin II activates I kappaB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis. Gastroenterology. 136:2334–2344. 2009. View Article : Google Scholar : PubMed/NCBI
26	Schwabe RF, Schnabl B, Kweon YO and Brenner DA: CD40 activates NF-kappa B and c-Jun N-terminal kinase and enhances chemokine secretion on activated human hepatic stellate cells. J Immunol. 166:6812–6819. 2001. View Article : Google Scholar : PubMed/NCBI
27	Elsharkawy AM, Wright MC, Hay RT, et al: Persistent activation of nuclear factor-kappaB in cultured rat hepatic stellate cells involves the induction of potentially novel Rel-like factors and prolonged changes in the expression of IkappaB family proteins. Hepatology. 30:761–769. 1999. View Article : Google Scholar
28	Kluwe J, Pradere JP, Gwak GY, et al: Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. Gastroenterology. 138:347–359. 2010. View Article : Google Scholar : PubMed/NCBI
29	Cushing TD, Metz DP, Whittington DA and McGee LR: PI3Kδ and PI3Kγ as targets for autoimmune and inflammatory diseases. J Med Chem. 55:8559–8581. 2012.
30	Jackson LN, Larson SD, Silva SR, et al: PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol. 294:G1401–G1410. 2008. View Article : Google Scholar : PubMed/NCBI