Tpl2 exaggerated ischemic hepatic injury through induction of apoptosis: Downstream of caspase-9



Ischemia-reperfusion injury is a dynamic process that involves the two interrelated phases of local ischemic insult and inflammation-mediated reperfusion injury, and an important cause of liver damage occurring during surgical procedures and represents the main underlying cause of graft dysfunction post-transplantation. This study is a highlight into innate-adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischemia-reperfusion. Tumor Progression Locus 2 (TPL2) is a serine-threonine kinase with essential functions in innate immune cells, where it transmits signals through Toll-like receptors family. To explore the role of Tpl2 in hepatic injury, liver ischemia/reperfusion injury was induced in wild type mice (Tpl2+/+) and in Tpl2-/- mice. They were sacrificed after 3-days post I/R. We determined TPL2 mRNA levels by quantitative PCR (qPCR), DNA and total RNA extraction from tissues was performed using the DNeasy and miRNeasy Kits, the extents of liver and function were studied. Tpl2 knockout mice produce low levels of proinflammatory cytokines expression, reduced release of LDH, ALT and less hepatic injury than wild type mice when exposed to I/R. Interestingly caspase-3 activation was significantly lower in Tpl2-/- mice. These results suggested that Tpl2 directly involved in apoptotic signal at the level of caspase-3 activation downstream of caspase-9, and that Tpl2 contributed to the exaggerated of ischemic liver injury through induction of apoptosis.

Keywords: Tpl2; Liver I/R; Caspase-3; Caspase-9; Proinflammatory cytokines

Copyright © 2015 by The American Society for BioMedicine and BM-Publisher, Inc.

Article citationReferencesFull-Text/PDFBecome reviewer
The citation data is computed by the following citation measuring services:

Google scholarcitedby


  1. Okajima K, Harada N, Uchiba M. Ranitidine reduces ischemia/reperfusion-induced liver injury in rats by inhibiting neutrophil activation. J Pharmacol Exp Ther 2002;301:1157–1165. [View In Article]
  2. Sakakura Y, Kaibori M, Oda M, Okumura T, Kwon AH, Kamiyama Y. Recombinant human hepatocyte growth factor protects the liver against hepatic ischemia and reperfusion injury in rats. J Surg Res 2000;92:261–266. [View In Article]
  3. Selzner N, Rudiger H, Graf R, Clavien P. Protective strategies against ischemic injury of the liver. Gastroenterology 2003; 125: 917–936. [PubMed]
  4. Vougioukalaki M, Kanellis DC, Gkouskou K, Eliopoulos AG. Tpl2 kinase signal transduction in inflammation and cancer. Cancer Lett 2011; 304(2):80–89. [PubMed]
  5. Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003; 284: G15–G26.
  6. Gracia-Sancho J, Villarreal G Jr, Zhang Y, Yu JX, Liu Y, Tullius SG. et al. Flow cessation triggers endothelial dysfunction during organ cold storage conditions: strategies for pharmacologic intervention. Transplantation 2010; 90: 142–149.[PubMed]
  7. Caraceni P, Domenicali M, Vendemiale G, Grattagliano I, Pertosa A, Nardo B. et al. The reduced tolerance of rat fatty liver to ischemia reperfusion is associated with mitochondrial oxidative injury. J Surg Res 2005;124:160–168. [Full Text PDF]
  8. Tsatsanis C, Patriotis C, Bear SE, Tsichlis PN. The Tpl-2 protooncoprotein activates the nuclear factor of activated T cells and induces interleukin 2 expression in T cell lines. Proc Natl Acad Sci USA 1998; 95(7):3827–3832. [PMC free article] [PubMed]
  9. Hessheimer AJ, Fondevila C, Taurá P, Muñoz J, Sánchez O., Fuster J. et al. Decompression of the portal bed and twice-baseline portal inflow are necessary for the functional recovery of a “small-for-size” graft. Ann Surg 2011; 253: 1201–1210. [PubMed]
  10. Schlegel A, Rougemont O, Graf R, Clavien PA, Dutkowski P. Protective mechanisms of end-ischemic cold machine perfusion in DCD liver grafts. J Hepatol 2013; 58: 278–286. [PubMed]
  11. Schiesser M, Wittert A, Nieuwenhuijs VB, Morphett A, Padbury RT, Barritt GJ. Intermittent ischemia but not ischemic preconditioning is effective in restoring bile flow after ischemia reperfusion injury in the livers of aged rats. J Surg Res 2009; 152: 61–68. [PubMed]
  12. Esposti DD, Domart MC, Sebagh M, Harper F, Pierron G,  Brenner C. et al. Autophagy is induced by ischemic preconditioning in human livers formerly treated by chemotherapy to limit necrosis. Autophagy 2010; 6: 172–174. [PubMed]
  13. Serracino-Inglott F, Habib NA, Mathie RT. Hepatic ischemia-reperfusion injury. Am J Surg  2001;181:160–166. [Full Text]
  14. Clemens MG. Nitric oxide in liver injury. Hepatology 1999; 30: 1–5. [Scopus] [PubMed]
  15. Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003; 284: G15-G26. [PubMed]
  16. Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthy SN, et al. Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J Clin Invest 2006; 116: 49-58. [PubMed]
  17. Imamura HBrault AHuet PMEffects of extended cold preservation and transplantation on the rat liver microcirculation. Hepatology 199725: 664671. [PDF(316K)]
  18. Guarrera JV, Estevez J, Boykin J et al. Hypothermic machine perfusion of liver grafts for transplantation: Technical development in human discard and miniature swine models. Transplant Proc 2005; 37: 323–325. [CrossRef] [PubMed]
  19. Lee CYZhang JXJones JW JrSouthard JHClemens MGFunctional recovery of preserved livers following warm ischemia: Improvement by machine perfusion preservationTransplantation 200274: 944951. [PubMed]
  20. Shinoda M Shimazu M Matsuda S et al. c-Jun N-terminal kinase activation during warm hepatic ischemia/reperfusion injuries in a rat model . Wound Repair Regen 2002 ; 10 : 314 – 319. [Full Article (HTML)]
  21. St Peter SDImber CJLopez IHughes DFriend PJExtended preservation of non-heart-beating donor livers with normothermic machine perfusionBr J Surg 200289: 609616. [Abstract]
  22. Imber CJSt Peter SDLopez de Cenarruzabeitia IPigott DJames TTaylor R, et al. Advantages of normothermic perfusion over cold storage in liver preservationTransplantation 200273: 701709. [PubMed]
  23. Lauschke HOlschewski PTolba RSchulz SMinor TOxygenated machine perfusion mitigates surface antigen expression and improves preservation of predamaged donor liversCryobiology 200346: 5360. [PubMed]
  24. Abu-Amara M, et al. Liver ischemia/reperfusion injury: Processes in inflammatory networks—a review. Liver Transpl 2010;16:1016–1032. [PubMed]
  25. Selzner N, Rudiger H, Graf R, Clavien PA. Protective strategies against ischemic injury of the liver. Gastroenterology 2003;125:917–936. [PubMed]
  26. Shen XD, et al. Inflammatory responses in a new mouse model of prolonged hepatic cold ischemia followed by arterialized orthotopic liver transplantation. Liver Transpl 2005;11:1273–1281. [PubMed]
  27. Land WG. The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation. Transplantation. 2005;79:505–514. [PubMed]
  28. Srikrishna G, Freeze HH. Endogenous damage-associated molecular pattern molecules at the crossroads of inflammation and cancer. Neoplasia. 2009;11:615–628. [PMC free article] [PubMed]
  29. Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann NY Acad Sci. 2008;1143:1–20. [PubMed]
  30. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010;140:805–820. [PubMed]
  31. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004;4:499–511. [PubMed]
  32. Pulskens WP, et al. Toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury. PLoS ONE. 2008;3:e3596. [PMC free article] [PubMed]
  33. Kaczorowski DJ, et al. Mechanisms of Toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart. Transplantation. 2009;87:1455–1463. [PMC free article] [PubMed]
  34. Shigeoka AA, et al. TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88- dependent and -independent pathways. J Immunol 2007;178:6252–6258. [PubMed]
  35. Ren F, et al. Inhibition of glycogen synthase kinase 3 beta ameliorates liver ischemia reperfusion injury by way of an interleukin-10-mediated immune regulatory mechanism. Hepatology 2011;54:687–696. [PMC free article] [PubMed]
  36. Dumitru CD, et al. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell. 2000;103(7):1071–1083. [PubMed]
  37. Fiorini RN, et al. Anti-endotoxin monoclonal antibodies are protective against hepatic ischemia/reperfusion injury in steatotic mice. Am J Transplant 2004;4:1567–1573. [PubMed]
  38. Bamboat ZM, et al. Toll-like receptor 9 inhibition confers protection from liver ischemiareperfusion injury. Hepatology 2009; 51:621–632. [PMC free article] [PubMed]
  39. Huang H, et al. Endogenous histones function as alarmins in sterile inflammatory liver injury through Toll-like receptor 9 in mice. Hepatology 2011; 54:999–1008. [PMC free article] [PubMed]
  40. Cavassani KA, et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med 2008; 205:2609–2621. [PMC free article] [PubMed]
  41. Kariko K, Ni H, Capodici J, Lamphier M, Weissman D. mRNA is an endogenous ligand for Toll-like receptor 3. J. Biol. Chem 2004; 279:12542–12550. [PubMed]
  42. Bone RC, Sibbald WJ, and Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 1992; 101:1481–1483. [PubMed]
  43. 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. 2006;102:17077–17082. [PMC free article] [PubMed]
  44. Wornle M, Schmid H, Banas B, Merkle M, Henger A, Roeder M, Blattner S, Bock E, Kretzler M, Grone HJ, Schlondorff D. Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis. Am. J. Pathol 2006;168:370–385. [PMC free article] [PubMed]
  45. Tabiasco J, Devevre E, Rufer N, Salaun B, Cerottini JC, Speiser D, Romero P. Human effector CD8+ T lymphocytes express TLR3 as a functional coreceptor. J. Immunol 2006;177:8708–8713. [PubMed]
  46. Yun Y, Zheng X, Chen L,Su Y, Kim C, Zhao M. Expression of ATF3 in mouse protects the liver against sepsis via inhibiting HMGB expression. American Journal of BioMedicine 2014; 2(3):337-349. [Abstract]

Who Can Become a Reviewer?
Any expert in the article's research field can become a reviewer with American Journal of Biomedicine. Editors might ask you to look at a specific aspect of an article,...

Find out more

Research Article
American Journal of BioMedicine 2015, Volume 3, Issue 1, pages 39-56
Received November 30, 2014; Accepted February 22, 2015, Published March 14, 2015

How to cite this articleJacob DH, Zeng IU, Tsung Y, et al. Tpl2 exaggerated ischemic hepatic injury through induction of apoptosis: Downstream of caspase-9. American Journal of BioMedicine 2015;3(1):39-56

Research article
1. Abstract
2. Keywords
3. Introduction
5. Results
6. Discussion
7. References

Article metric