Inhibition of IRF3 expression reduces TGF-β1-induced proliferation of hepatic stellate cells

详细信息    查看全文

• 作者：Ming-ming Ni ; Tao Xu ; Ya-rui Wang ; Ying-hua He…
• 关键词：IRF3 ; Hepatic stellate cell ; AKT ; Liver fibrosis
• 刊名：Journal of Physiology and Biochemistry
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：72
• 期：1
• 页码：9-23
• 全文大小：1,428 KB
• 参考文献：1.Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115(2):209–218. doi:10.​1172/​JCI24282 PubMedCentral CrossRef PubMed
  2.Chen RJ, Wu HH, Wang YJ (2015) Strategies to prevent and reverse liver fibrosis in humans and laboratory animals. Arch Toxicol. doi:10.​1007/​s00204-015-1525-6
  3.Dong S, Wu C, Hu J, Wang Q, Chen S, Wang Z, Xiong W (2015) Wnt5a promotes cytokines production and cell proliferation in human hepatic stellate cells independent of canonical Wnt pathway. Clin Lab 61(5–6):537–547PubMed
  4.Dusabineza AC, Najimi M, van Hul N, Legry V, Khuu DN, van Grunsven LA, Sokal E, Leclercq IA (2015) Hepatic stellate cells improve engraftment of human primary hepatocytes: a pre-clinical transplantation study in animal model. Cell Transplant. doi:10.​3727/​096368915X686788​ PubMed
  5.Elpek GO (2014) Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: an update. World J Gastroenterol WJG 20(23):7260–7276. doi:10.​3748/​wjg.​v20.​i23.​7260 CrossRef PubMed
  6.Friedman SL (2008) Hepatic fibrosis—overview. Toxicology 254(3):120–129. doi:10.​1016/​j.​tox.​2008.​06.​013 CrossRef PubMed
  7.Fallowfield JA (2011) Therapeutic targets in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 300(5):G709–G715. doi:10.​1152/​ajpgi.​00451.​2010 CrossRef PubMed
  8.Guo S, Li ZZ, Jiang DS, Lu YY, Liu Y, Gao L, Zhang SM, Lei H, Zhu LH, Zhang XD, Liu DP, Li H (2014) IRF4 is a novel mediator for neuronal survival in ischaemic stroke. Cell Death Differ 21(6):888–903. doi:10.​1038/​cdd.​2014.​9 PubMedCentral CrossRef PubMed
  9.Herrmann J, Gressner AM, Weiskirchen R (2007) Immortal hepatic stellate cell lines: useful tools to study hepatic stellate cell biology and function? J Cell Mol Med 11(4):704–722. doi:10.​1111/​j.​1582-4934.​2007.​00060.​x PubMedCentral CrossRef PubMed
  10.Hiscott J, Pitha P, Genin P, Nguyen H, Heylbroeck C, Mamane Y, Algarte M, Lin R (1999) Triggering the interferon response: the role of IRF-3 transcription factor. J Interf Cytok Res Offic J Intern Soc Interf Cytok Res 19(1):1–13. doi:10.​1089/​107999099314360 CrossRef
  11.Horiuchi M, Yamada H, Akishita M, Ito M, Tamura K, Dzau VJ (1999) Interferon regulatory factors regulate interleukin-1β-converting enzyme expression and apoptosis in vascular smooth muscle cells. Hypertension 33(1):162–166CrossRef PubMed
  12.Hernandez-Gea V, Friedman SL (2011) Pathogenesis of liver fibrosis. Annu Rev Pathol 6:425–456. doi:10.​1146/​annurev-pathol-011110-130246 CrossRef PubMed
  13.Honda K, Taniguchi T (2006) IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 6(9):644–658. doi:10.​1038/​nri1900 CrossRef PubMed
  14.Inagaki Y, Okazaki I (2007) Emerging insights into transforming growth factor β Smad signal in hepatic fibrogenesis. Gut 56(2):284–292. doi:10.​1136/​gut.​2005.​088690 PubMedCentral CrossRef PubMed
  15.Kang L, Wang Y, Zhang M, Sun R, Lou Y, Wang Y, Li D (2014) Effect of Huazhuojiedu medicated serum on the proliferation and activation of hepatic stellate cells and the expression of PI3K and p-Akt in rats. Int J Clin Experiment Med 7(10):3280–3288
  16.Kanakachari M, Solanke AU, Prabhakaran N, Ahmad I, Dhandapani G, Jayabalan N, Kumar PA (2015) Evaluation of suitable reference genes for normalization of qPCR gene expression studies in Brinjal (Solanum melongena L.) during fruit developmental stages. Appl Biochem Biotechnol. doi:10.​1007/​s12010-015-1884-8 PubMed
  17.Kisseleva T, Brenner DA (2007) Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis. J Gastroenterol Hepatol 22(Suppl 1):S73–S78. doi:10.​1111/​j.​1440-1746.​2006.​04658.​x CrossRef PubMed
  18.Karsdal MA, Manon-Jensen T, Genovese F, Kristensen JH, Nielsen MJ, Sand JM, Hansen NU, Bay-Jensen AC, Bager CL, Krag A, Blanchard A, Krarup H, Leeming DJ, Schuppan D (2015) Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 308(10):G807–G830. doi:10.​1152/​ajpgi.​00447.​2014 CrossRef PubMed
  19.Loi P, Yuan Q, Torres D, Delbauve S, Laute MA, Lalmand MC, Petein M, Goriely S, Goldman M, Flamand V (2013) Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury. Hepatology 57(1):351–361. doi:10.​1002/​hep.​26022 CrossRef PubMed
  20.Liu X, Hu H, Yin JQ (2006) Therapeutic strategies against TGF-β signaling pathway in hepatic fibrosis. Liver Int Offic J Intern Assoc Stud Liver 26(1):8–22. doi:10.​1111/​j.​1478-3231.​2005.​01192.​x CrossRef
  21.Puche JE, Saiman Y, Friedman SL (2013) Hepatic stellate cells and liver fibrosis. Comprehen Physiol 3(4):1473–1492. doi:10.​1002/​cphy.​c120035 CrossRef
  22.Petrasek J, Dolganiuc A, Csak T, Nath B, Hritz I, Kodys K, Catalano D, Kurt-Jones E, Mandrekar P, Szabo G (2011) Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells. Hepatology 53(2):649–660. doi:10.​1002/​hep.​24059 PubMedCentral CrossRef PubMed
  23.Qashqari H, Al-Mars A, Chaudhary A, Abuzenadah A, Damanhouri G, Alqahtani M, Mahmoud M, El Sayed ZM, Fatima K, Qadri I (2013) Understanding the molecular mechanism(s) of hepatitis C virus (HCV)-induced interferon resistance. Infect Genet Evol J Molecul Epidemiol Evol Genet Infect Dis 19:113–119. doi:10.​1016/​j.​meegid.​2013.​06.​025 CrossRef
  24.Savitsky D, Tamura T, Yanai H, Taniguchi T (2010) Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol Immunother CII 59(4):489–510. doi:10.​1007/​s00262-009-0804-6 CrossRef PubMed
  25.Son MK, Ryu YL, Jung KH, Lee H, Lee HS, Yan HH, Park HJ, Ryu JK, Suh JK, Hong S, Hong SS (2013) HS-173, a novel PI3K inhibitor, attenuates the activation of hepatic stellate cells in liver fibrosis. Sci Rep 3:3470. doi:10.​1038/​srep03470 PubMedCentral CrossRef PubMed
  26.Tarassishin L, Suh HS, Lee SC (2011) Interferon regulatory factor 3 plays an anti-inflammatory role in microglia by activating the PI3K/Akt pathway. J Neuroinflammation 8:187. doi:10.​1186/​1742-2094-8-187 PubMedCentral CrossRef PubMed
  27.Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, Hsu CC, Pradere JP, Friedman RA, Schwabe RF (2012) Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143(4):1073–1083. doi:10.​1053/​j.​gastro.​2012.​06.​036 , e1022CrossRef PubMed
  28.Tsushima K, Osawa T, Yanai H, Nakajima A, Takaoka A, Manabe I, Ohba Y, Imai Y, Taniguchi T, Nagai R (2011) IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II-induced hypertension. FASEB J Offic Public Federat Am Soc Exp Biol 25(5):1531–1543. doi:10.​1096/​fj.​10-174615 CrossRef
  29.van der Meer AJ, Sonneveld M, Schouten JN, Janssen HL (2014) [Reversibility of hepatic fibrosis]. Nederlands tijdschrift voor geneeskunde 158:A6790
  30.Wells RG (2005) The role of matrix stiffness in hepatic stellate cell activation and liver fibrosis. J Clin Gastroenterol 39(4 Suppl 2):S158–S161CrossRef PubMed
  31.Ysebrant de Lendonck L, Martinet V, Goriely S (2014) Interferon regulatory factor 3 in adaptive immune responses. Cellul Molecul Life Sci CMLS 71(20):3873–3883. doi:10.​1007/​s00018-014-1653-9 CrossRef
  32.Yin C, Evason KJ, Asahina K, Stainier DY (2013) Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest 123(5):1902–1910. doi:10.​1172/​JCI66369 PubMedCentral CrossRef PubMed
  33.Zhao GN, Jiang DS, Li H (2015) Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease. Biochim Biophys Acta 1852(2):365–378. doi:10.​1016/​j.​bbadis.​2014.​04.​030 CrossRef PubMed
  34.Zhang S, Sun WY, Wu JJ, Wei W (2014) TGF-β signaling pathway as a pharmacological target in liver diseases. Pharmacol Res Offic J Ital Pharmacol Soc 85:15–22. doi:10.​1016/​j.​phrs.​2014.​05.​005
  
• 作者单位：Ming-ming Ni (1) (2)
  Tao Xu (1) (2)
  Ya-rui Wang (1) (2)
  Ying-hua He (1) (2)
  Qun Zhou (1) (2)
  Cheng Huang (1) (2)
  Xiao-ming Meng (1) (2)
  Jun Li (1) (2) (3)
  
  1. School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, 230032, China
  2. Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, 230032, China
  3. School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province, 230032, China
  
• 刊物主题：Biomedicine general; Human Physiology; Animal Physiology;
• 出版者：Springer Netherlands
• ISSN：1877-8755

文摘

Therapeutic management of liver fibrosis remains an unresolved clinical problem. Activation of hepatic stellate cell (HSC) is a pivotal event in the progression of liver fibrosis. Recent reports have showed that inhibition of activated HSC proliferation contributes to the reversal of liver fibrosis. Interferon regulatory factor 3 (IRF3), one member of the interferon regulatory factor (IRF) family, is recently proven to be a critical modulator in cardiac fibrosis. And accumulating evidence demonstrated that IRF3 plays a crucial role in liver diseases, such as hepatic steatosis, liver inflammation, and alcoholic liver injury. However, the understanding of the function of IRF3 in liver fibrosis remains limited. Our results identified the role of IRF3 in regulating human HSC (LX-2 cell) cell proliferation and apoptosis. The present study indicated that the expression of IRF3 was significantly increased in HSCs in response to TGF-β1 stimulation. Moreover, a stable and unlimited source of human HSC, the LX-2 cell line, transfected with IRF3-siRNA significantly decreases the expression level of type I collagen (Col1a1) and α-smooth muscle actin (α-SMA) in activated LX-2 cells. On the contrary, overexpression of IRF3 gives rise to an upregulation of Col1a1 and α-SMA in LX-2 cells, and further promoted HSC proliferation. Moreover, the inhibition of IRF3 significantly suppressed TGF-β1-induced HSC proliferation and increased its apoptosis. Of note, the present study indicated IRF3 may regulate LX-2 cell proliferation by via AKT signaling pathway. In summary, these observations suggest IRF3 may function as a novel regulator to modulate TGF-β1-induced LX-2 proliferation, at least in part, via AKT signaling pathway.