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Open Access 01-12-2018 | Research article

Interference with KCTD9 inhibits NK cell activation and ameliorates fulminant liver failure in mice

Authors: Xiaoping Zhang, Lin Zhu, Yaoyong Zhou, Aichao Shi, Hongwu Wang, Meifang Han, Xiaoyang Wan, Semvua Bukheti Kilonzo, Xiaoping Luo, Tao Chen, Qin Ning

Published in: BMC Immunology | Issue 1/2018

Abstract

Background

Potassium channel tetramerisation domain containing 9 (KCTD9), a member of KCTD family with a DNA-like pentapeptide repeat domain, was found to be increased particularly in NK cells of patients with HBV-induced acute-on-chronic liver failure (HBV-ACLF) and experimental viral fulminant hepatitis. Knockdown of KCTD9 in immortalized NK cells inhibits cytokines production and cytotoxicity. As NK cell activation was shown to exacerbate liver damage in viral fulminant hepatitis, we propose that target inhibition of KCTD9 may prohibit NK cells activity and thus ameliorate liver damage in viral fulminant hepatitis.

Result

Hydrodynamic delivery of plasmid expressing short-hairpin RNA against KCTD9 resulted in impaired NK cells function as demonstrated by reduced cytokine production and cytotoxicity, and ameliorated liver injury as manifested by improved liver histology and survival rate. In contrast, delivery of plasmid expressing KCTD9 led to deteriorated disease progression.

Conclusion

Interference with KCTD9 expression exert beneficial effect in viral fulminant hepatitis therapy. Such effect may be mediated by impairment of NK cell activation.

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Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386(10003):1546–55.CrossRefPubMed

Sarin SK, Choudhury A. Acute-on-chronic liver failure. Curr Gastroenterol Rep. 2016;18(12):61.CrossRefPubMed

Ochi M, Ohdan H, Mitsuta H, Onoe T, Tokita D, Hara H, Ishiyama K, Zhou W, Tanaka Y, Asahara T. Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice. Hepatology. 2004;39(5):1321–31.CrossRefPubMed

Chen Y, Wei H, Sun R, Dong Z, Zhang J, Tian Z. Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells. Hepatology. 2007;46(3):706–15.CrossRefPubMed

Tosello-Trampont AC, Krueger P, Narayanan S, Landes SG, Leitinger N, Hahn YS. NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology. 2016;63(3):799–812.CrossRefPubMedPubMedCentral

Zou Y, Chen T, Han M, Wang H, Yan W, Song G, Wu Z, Wang X, Zhu C, Luo X, et al. Increased killing of liver NK cells by Fas/Fas ligand and NKG2D/NKG2D ligand contributes to hepatocyte necrosis in virus-induced liver failure. J Immunol. 2010;184(1):466–75.CrossRefPubMed

Skoblov M, Marakhonov A, Marakasova E, Guskova A, Chandhoke V, Birerdinc A, Baranova A. Protein partners of KCTD proteins provide insights about their functional roles in cell differentiation and vertebrate development. Bioessays. 2013;35(7):586–96.CrossRefPubMed

Hegde SS, Vetting MW, Mitchenall LA, Maxwell A, Blanchard JS. Structural and biochemical analysis of the pentapeptide repeat protein EfsQnr, a potent DNA gyrase inhibitor. Antimicrob Agents Chemother. 2011;55(1):110–7.CrossRefPubMed

Merens A, Matrat S, Aubry A, Lascols C, Jarlier V, Soussy CJ, Cavallo JD, Cambau E. The pentapeptide repeat proteins MfpAMt and QnrB4 exhibit opposite effects on DNA gyrase catalytic reactions and on the ternary gyrase-DNA-quinolone complex. J Bacteriol. 2009;191(5):1587–94.CrossRefPubMed

10.

Banno H, Chua NH. Characterization of the arabidopsis formin-like protein AFH1 and its interacting protein. Plant Cell Physiol. 2000;41(5):617–26.CrossRefPubMed

11.

Ji AX, Chu A, Nielsen TK, Benlekbir S, Rubinstein JL, Prive GG. Structural insights into KCTD protein assembly and Cullin3 recognition. J Mol Biol. 2016;428(1):92–107.CrossRefPubMed

12.

Chen T, Zhu L, Zhou Y, Pi B, Liu X, Deng G, Zhang R, Wang Y, Wu Z, Han M, et al. KCTD9 contributes to liver injury through NK cell activation during hepatitis B virus-induced acute-on-chronic liver failure. Clin Immunol. 2013;146(3):207–16.CrossRefPubMed

13.

Zhou YY, Pi B, Liu XJ, Zhang R, Deng GH, Chen T, Wang HW, Han MF, Yan WM, Xi D, et al. Increased expression of KCTD9, a novel potassium channel related gene, correlates with disease severity in patients with viral hepatitis B. Zhonghua Gan Zang Bing Za Zhi. 2008;16(11):835–9.PubMed

14.

Marsden PA, Ning Q, Fung LS, Luo X, Chen Y, Mendicino M, Ghanekar A, Scott JA, Miller T, Chan CW, et al. The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis. J Clin Invest. 2003;112(1):58–66.CrossRefPubMedPubMedCentral

15.

Fung LS, Neil G, Leibowitz J, Cole EH, Chung S, Crow A, Levy GA. Monoclonal antibody analysis of a unique macrophage procoagulant activity induced by murine hepatitis virus strain 3 infection. J Biol Chem. 1991;266(3):1789–95.PubMed

16.

Moore CB, Guthrie EH, Huang MT, Taxman DJ. Short hairpin RNA (shRNA): design, delivery, and assessment of gene knockdown. Methods Mol Biol. 2010;629:141–58.PubMedPubMedCentral

17.

Gao S, Wang M, Ye H, Guo J, Xi D, Wang Z, Zhu C, Yan W, Luo X, Ning Q. Dual interference with novel genes mfgl2 and mTNFR1 ameliorates murine hepatitis virus type 3-induced fulminant hepatitis in BALB/cJ mice. Hum Gene Ther. 2010;21(8):969–77.CrossRefPubMed

18.

Nakayama Y, Shimizu Y, Hirano K, Ebata K, Minemura M, Watanabe A, Sugiyama T. CTLA-4Ig suppresses liver injury by inhibiting acquired immune responses in a mouse model of fulminant hepatitis. Hepatology. 2005;42(4):915–24.CrossRefPubMed

19.

Arvelo MB, Cooper JT, Longo C, Daniel S, Grey ST, Mahiou J, Czismadia E, Abu-Jawdeh G, Ferran C. A20 protects mice from D-galactosamine/lipopolysaccharide acute toxic lethal hepatitis. Hepatology. 2002;35(3):535–43.CrossRefPubMed

20.

Song YM, Chen MD. Zinc supplementation attenuates thioacetamide-induced liver injury and hyperglycemia in mice. Biol Trace Elem Res. 2003;92(2):173–80.CrossRefPubMed

21.

Zhu P, Duan L, Chen J, Xiong A, Xu Q, Zhang H, Zheng F, Tan Z, Gong F, Fang M. Gene silencing of NALP3 protects against liver ischemia-reperfusion injury in mice. Hum Gene Ther. 2011;22(7):853–64.CrossRefPubMed

22.

Ke B, Shen XD, Gao F, Qiao B, Ji H, Busuttil RW, Volk HD, Kupiec-Weglinski JW. Small interfering RNA targeting heme oxygenase-1 (HO-1) reinforces liver apoptosis induced by ischemia-reperfusion injury in mice: HO-1 is necessary for cytoprotection. Hum Gene Ther. 2009;20(10):1133–42.CrossRefPubMedPubMedCentral

23.

Saito Y, Kon S, Fujiwara Y, Nakayama Y, Kurotaki D, Fukuda N, Kimura C, Kanayama M, Ito K, Diao H, et al. Osteopontin small interfering RNA protects mice from fulminant hepatitis. Hum Gene Ther. 2007;18(12):1205–14.CrossRefPubMed

24.

Kang JH, Toita R, Murata M. Liver cell-targeted delivery of therapeutic molecules. Crit Rev Biotechnol. 2016;36(1):132–43.CrossRefPubMed

25.

Nayak S, Herzog RW. Progress and prospects: immune responses to viral vectors. Gene Ther. 2010;17(3):295–304.CrossRefPubMed

26.

Sun CP, Wu TH, Chen CC, Wu PY, Shih YM, Tsuneyama K, Tao MH. Studies of efficacy and liver toxicity related to adeno-associated virus-mediated RNA interference. Hum Gene Ther. 2013;24(8):739–50.CrossRefPubMedPubMedCentral

27.

Chen SH, Wu HL, Kao JH, Hwang LH. Persistent hepatitis B viral replication in a FVB/N mouse model: impact of host and viral factors. PLoS One. 2012;7(5):e36984.CrossRefPubMedPubMedCentral

28.

Wu Z, Han M, Chen T, Yan W, Ning Q. Acute liver failure: mechanisms of immune-mediated liver injury. Liver International. 2010;30(6):782–94.CrossRefPubMed

29.

Lindholm CK, Gylfe E, Zhang W, Samelson LE, Welsh M. Requirement of the Src homology 2 domain protein Shb for T cell receptor-dependent activation of the interleukin-2 gene nuclear factor for activation of T cells element in Jurkat T cells. J Biol Chem. 1999;274(39):28050–7.CrossRefPubMed

30.

Lindholm CK. IL-2 receptor signaling through the Shb adapter protein in T and NK cells. Biochem Biophys Res Commun. 2002;296(4):929–36.CrossRefPubMed

31.

Dixelius J, Larsson H, Sasaki T, Holmqvist K, Lu L, Engstrom A, Timpl R, Welsh M, Claesson-Welsh L. Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood. 2000;95(11):3403–11.PubMed

32.

Latour S, Roncagalli R, Chen R, Bakinowski M, Shi X, Schwartzberg PL, Davidson D, Veillette A. Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation. Nat Cell Biol. 2003;5(2):149–54.CrossRefPubMed

33.

Welsh M, Songyang Z, Frantz JD, Trub T, Reedquist KA, Karlsson T, Miyazaki M, Cantley LC, Band H, Shoelson SE. Stimulation through the T cell receptor leads to interactions between SHB and several signaling proteins. Oncogene. 1998;16(7):891–901.CrossRefPubMed

34.

Malissen B, Gregoire C, Malissen M, Roncagalli R. Integrative biology of T cell activation. Nat Immunol. 2014;15(9):790–7.CrossRefPubMed

Title: Interference with KCTD9 inhibits NK cell activation and ameliorates fulminant liver failure in mice
Authors: Xiaoping Zhang
Lin Zhu
Yaoyong Zhou
Aichao Shi
Hongwu Wang
Meifang Han
Xiaoyang Wan
Semvua Bukheti Kilonzo
Xiaoping Luo
Tao Chen
Qin Ning
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Immunology / Issue 1/2018
Electronic ISSN: 1471-2172
DOI: https://doi.org/10.1186/s12865-018-0256-x

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Interference with KCTD9 inhibits NK cell activation and ameliorates fulminant liver failure in mice

Abstract

Background

Result

Conclusion

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