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Protective effect of Gö6976, a PKD inhibitor, on LPS/d-GalN-induced acute liver injury in mice

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Abstract

Objective

Protein kinase D (PKD) is a newly described serine/threonine protein kinase that plays a pivotal role in inflammatory response. In the present study, we examined the protective effect of Gö6976, a PKD inhibitor, on lipopolysaccharide (LPS) and d-galactosamine (d-GalN)-induced acute liver injury in mice.

Materials and methods

Mice were pretreated intraperitoneally with Gö6976 30 min before LPS/d-GalN administration . The mortality and degree of hepatic injury was subsequently assessed.

Results

The results indicated that LPS/d-GalN administration markedly induced hepatic PKD activation, lethality and liver injury, while pretreatment of the PKD inhibitor Gö6976 significantly inhibited LPS-induced PKD activation, improved the survival of LPS/d-GalN-administered mice and attenuated LPS/d-GalN-induced liver injury, as evidenced by reduced levels of serum aminotransferases as well as reduced histopathological changes. In addition, the protective effects of Gö6976 were paralleled by suppressed activation of mitogen-activated protein kinases (MAPKs), decreased expression of tumor necrosis factor-α (TNF-α) and adhesion molecules, and reduced apoptosis and myeloperoxidase (MPO) activity in liver.

Conclusions

Our experimental data indicated that Gö6976, a PKD inhibitor, could effectively prevent LPS/d-GalN-induced acute liver injury by inhibition of MAPKs activation to reduce TNF-α production. This suggests the potential pharmacological value of PKD inhibitors in the intervention of inflammation-based liver diseases.

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References

  1. Rykx A, De Kimpe L, Mikhalap S, Vantus T, Seufferlein T, Vandenheede JR, et al. Protein kinase D: a family affair. FEBS Lett. 2003;546:81–6.

    Article  PubMed  CAS  Google Scholar 

  2. Rozengurt E, Rey O, Waldron RT. Protein kinase D signaling. J Biol Chem. 2005;280:13205–8.

    Article  PubMed  CAS  Google Scholar 

  3. Wang QJ. PKD at the crossroads of DAG and PKC signaling. Trends Pharmacol Sci. 2006;27:317–23.

    Article  PubMed  CAS  Google Scholar 

  4. Ivison SM, Graham NR, Bernales CQ, Kifayet A, Ng N, Shobab LA, et al. Protein kinase D interaction with TLR5 is required for inflammatory signaling in response to bacterial flagellin. J Immunol. 2007;178:5735–43.

    PubMed  CAS  Google Scholar 

  5. Park JE, Kim YI, Yi AK. Protein kinase D1 is essential for MyD88-dependent TLR signaling pathway. J Immunol. 2009;182:6316–27.

    Article  PubMed  CAS  Google Scholar 

  6. Park JE, Kim YI, Yi AK. Protein kinase D1: a new component in TLR9 signaling. J Immunol. 2008;181:2044–55.

    PubMed  CAS  Google Scholar 

  7. Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann NY Acad Sci. 2008;1143:1–20.

    Article  PubMed  CAS  Google Scholar 

  8. Marshall JC. Lipopolysaccharide: an endotoxin or an exogenous hormone? Clin Infect Dis. 2005;41(Suppl 7):S470–80.

    Article  PubMed  CAS  Google Scholar 

  9. Dhainaut JF, Marin N, Mignon A, Vinsonneau C. Hepatic response to sepsis: interaction between coagulation and inflammatory processes. Crit Care Med. 2001;29:S42–7.

    Article  PubMed  CAS  Google Scholar 

  10. Abraham E, Singer M. Mechanisms of sepsis-induced organ dysfunction. Crit Care Med. 2007;35:2408–16.

    Article  PubMed  Google Scholar 

  11. Song MJ, Wang YQ, Wu GC. Lipopolysaccharide-induced protein kinase D activation mediated by interleukin-1beta and protein kinase C. Brain Res. 2007;1145:19–27.

    Article  PubMed  CAS  Google Scholar 

  12. Zhang W, Zheng S, Storz P, Min W. Protein kinase D specifically mediates apoptosis signal-regulating kinase 1-JNK signaling induced by H2O2 but not tumor necrosis factor. J Biol Chem. 2005;280:19036–44.

    Article  PubMed  CAS  Google Scholar 

  13. Silverstein R. d-Galactosamine lethality model: scope and limitations. J Endotoxin Res. 2004;10:147–62.

    PubMed  CAS  Google Scholar 

  14. Wilhelm EA, Jesse CR, Roman SS, Nogueira CW, Savegnago L. Hepatoprotective effect of 3-alkynyl selenophene on acute liver injury induced by d-galactosamine and lipopolysaccharide. Exp Mol Pathol. 2009;87:20–6.

    Article  PubMed  CAS  Google Scholar 

  15. Tran-Thi TA, Phillips J, Falk H, Decker K. Toxicity of d-galactosamine for rat hepatocytes in monolayer culture. Exp Mol Pathol. 1985;42:89–116.

    Article  PubMed  CAS  Google Scholar 

  16. Ren M, Feng H, Fu Y, Land M, Rubin CS. Protein kinase D is an essential regulator of C. elegans innate immunity. Immunity. 2009;30:521–32.

    Article  PubMed  CAS  Google Scholar 

  17. Johannes FJ, Prestle J, Eis S, Oberhagemann P, Pfizenmaier K. PKCu is a novel, atypical member of the protein kinase C family. J Biol Chem. 1994;269:6140–8.

    PubMed  CAS  Google Scholar 

  18. Dauphinee SM, Karsan A. Lipopolysaccharide signaling in endothelial cells. Lab Invest. 2006;86:9–22.

    Article  PubMed  CAS  Google Scholar 

  19. Kitazawa T, Tsujimoto T, Kawaratani H, Fujimoto M, Fukui H. Expression of toll-like receptor 4 in various organs in rats with d-galactosamine-induced acute hepatic failure. J Gastroenterol Hepatol. 2008;23:e494–8.

    Article  PubMed  CAS  Google Scholar 

  20. Gaestel M, Mengel A, Bothe U, Asadullah K. Protein kinases as small molecule inhibitor targets in inflammation. Curr Med Chem. 2007;14:2214–34.

    Article  PubMed  CAS  Google Scholar 

  21. Iida C, Fujii K, Kishioka T, Nagae R, Onishi Y, Ichi I, et al. Activation of mitogen activated protein kinase (MAPK) during carbon tetrachloride intoxication in the rat liver. Arch Toxicol. 2007;81:489–93.

    Article  PubMed  CAS  Google Scholar 

  22. Cursio R, Filippa N, Miele C, Van Obberghen E, Gugenheim J. Involvement of protein kinase B and mitogen-activated protein kinases in experimental normothermic liver ischaemia–reperfusion injury. Br J Surg. 2006;93:752–61.

    Article  PubMed  CAS  Google Scholar 

  23. Klintman D, Li X, Santen S, Schramm R, Jeppsson B, Thorlacius H. p38 mitogen-activated protein kinase-dependent chemokine production, leukocyte recruitment, and hepatocellular apoptosis in endotoxemic liver injury. Ann Surg 2005; 242:830–8 (discussion 838–9).

    Google Scholar 

  24. Takamura M, Matsuda Y, Yamagiwa S, Tamura Y, Honda Y, Suzuki K, et al. An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from d-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins. Life Sci. 2007;80:1335–44.

    Article  PubMed  CAS  Google Scholar 

  25. Freudenberg MA, Keppler D, Galanos C. Requirement for lipopolysaccharide-responsive macrophages in galactosamine-induced sensitization to endotoxin. Infect Immun. 1986;51:891–5.

    PubMed  CAS  Google Scholar 

  26. Dong L, Zuo L, Xia S, Gao S, Zhang C, Chen J, et al. Reduction of liver tumor necrosis factor-alpha expression by targeting delivery of antisense oligonucleotides into Kupffer cells protects rats from fulminant hepatitis. J Gene Med. 2009;11:229–39.

    Article  PubMed  CAS  Google Scholar 

  27. Jiang W, Sun R, Wei H, Tian Z. Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. Proc Natl Acad Sci USA. 2005;102:17077–82.

    Article  PubMed  CAS  Google Scholar 

  28. Masubuchi Y, Horie T. Endotoxin-mediated disturbance of hepatic cytochrome P450 function and development of endotoxin tolerance in the rat model of dextran sulfate sodium-induced experimental colitis. Drug Metab Dispos. 2004;32:437–41.

    Article  PubMed  CAS  Google Scholar 

  29. Leist M, Gantner F, Bohlinger I, Tiegs G, Germann PG, Wendel A. Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models. Am J Pathol. 1995;146:1220–34.

    PubMed  CAS  Google Scholar 

  30. Fiedler VB, Loof I, Sander E, Voehringer V, Galanos C, Fournel MA. Monoclonal antibody to tumor necrosis factor–alpha prevents lethal endotoxin sepsis in adult rhesus monkeys. J Lab Clin Med. 1992;120:574–88.

    PubMed  CAS  Google Scholar 

  31. Hatano E. Tumor necrosis factor signaling in hepatocyte apoptosis. J Gastroenterol Hepatol. 2007;22(1):S43–4.

    Article  PubMed  CAS  Google Scholar 

  32. Faubion WA, Gores GJ. Death receptors in liver biology and pathobiology. Hepatology. 1999;29:1–4.

    Article  PubMed  CAS  Google Scholar 

  33. Porter AG, Janicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999;6:99–104.

    Article  PubMed  CAS  Google Scholar 

  34. Schlayer HJ, Laaff H, Peters T, Woort-Menker M, Estler HC, Karck U, et al. Involvement of tumor necrosis factor in endotoxin-triggered neutrophil adherence to sinusoidal endothelial cells of mouse liver and its modulation in acute phase. J Hepatol. 1988;7:239–49.

    Article  PubMed  CAS  Google Scholar 

  35. Jaeschke H, Hasegawa T. Role of neutrophils in acute inflammatory liver injury. Liver Int. 2006;26:912–9.

    Article  PubMed  CAS  Google Scholar 

  36. Steeber DA, Tedder TF. Adhesion molecule cascades direct lymphocyte recirculation and leukocyte migration during inflammation. Immunol Res. 2000;22:299–317.

    Article  PubMed  CAS  Google Scholar 

  37. Ohira H, Abe K, Yokokawa J, Takiguchi J, Rai T, Shishido S, et al. Adhesion molecules and CXC chemokines in endotoxin-induced liver injury. Fukushima J Med Sci. 2003;49:1–13.

    PubMed  CAS  Google Scholar 

  38. Xiang L, Klintman D, Thorlacius H. Allopurinol inhibits CXC chemokine expression and leukocyte adhesion in endotoxemic liver injury. Inflamm Res. 2003;52:353–8.

    Article  PubMed  CAS  Google Scholar 

  39. Xu H, Gonzalo JA, St Pierre Y, Williams IR, Kupper TS, Cotran RS, et al. Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice. J Exp Med. 1994;180:95–109.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 30772251, 30700289).

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Authors and Affiliations

  1. Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China

    G. J. Duan, J. Zhu, C. Y. Xu, X. D. Ge, L. M. Liu & Y. S. Liu

  2. Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China

    J. Y. Wan

  3. Department of Pathophysiology, Chongqing Medical University, Chongqing, 400016, China

    L. Zhang

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  1. G. J. Duan
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  2. J. Zhu
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  3. C. Y. Xu
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  6. X. D. Ge
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  7. L. M. Liu
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Correspondence to Y. S. Liu.

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Responsible Editor: Graham Wallace.

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Duan, G.J., Zhu, J., Xu, C.Y. et al. Protective effect of Gö6976, a PKD inhibitor, on LPS/d-GalN-induced acute liver injury in mice. Inflamm. Res. 60, 357–366 (2011). https://doi.org/10.1007/s00011-010-0278-1

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  • DOI: https://doi.org/10.1007/s00011-010-0278-1

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