Inhibition of sphingosine kinase-2 suppresses inflammation and attenuates graft injury after liver transplantation in rats

Qinlong Liu, Hasibur Rehman, Yanjun Shi, Yasodha Krishnasamy, John J. Lemasters, Charles Smith, Zhi Zhong

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Inflammation mediates/promotes graft injury after liver transplantation (LT). This study investigated the roles of sphingosine kinase-2 (SK2) in inflammation after LT. Liver grafts were stored in UW solution with and without ABC294640 (100 μM), a selective inhibitor of SK2, before implantation. Hepatic sphingosine-1-phosphate (S1P) levels increased ~4-fold after LT, which was blunted by 40% by ABC294640. Hepatic toll-like receptor-4 (TLR4) expression and nuclear factor-κB (NF-κB) p65 subunit phosphorylation elevated substantially after transplantation. The pro-inflammatory cytokines/chemokines tumor necrosis factor-α, interleukin-1β and C-X-C motif chemokine 10 mRNAs increased 5.9-fold, 6.1-fold and 16-fold, respectively following transplantation, while intrahepatic adhesion molecule-1 increased 5.7-fold and monocytes/macrophage and neutrophil infiltration and expansion of residential macrophage population increased 7.8-13.4 fold, indicating enhanced inflammation. CD4+ T cell infiltration and interferon-γ production also increased. ABC294640 blunted TLR4 expression by 60%, NF-κB activation by 84%, proinflammatory cytokine/chemokine production by 45-72%, adhesion molecule expression by 54% and infiltration of monocytes/macrophages and neutrophils by 62-67%. ABC294640 also largely blocked CD4+ T cell infiltration and interferon-γ production. Focal necrosis and apoptosis occurred after transplantation with serum alanine aminotransferase (ALT) reaching ~6000 U/L and serum total bilirubin elevating to ~1.5 mg/dL. Inhibition of SK2 by ABC294640 blunted necrosis by 57%, apoptosis by 74%, ALT release by ~68%, and hyperbilirubinemia by 74%. Most importantly, ABC294640 also increased survival from ~25% to ~85%. In conclusion, SK2 plays an important role in hepatic inflammation responses and graft injury after cold storage/transplantation and represents a new therapeutic target for liver graft failure.

Original languageEnglish (US)
Article numbere41834
JournalPloS one
Volume7
Issue number7
DOIs
StatePublished - Jul 25 2012

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Transplantation (surgical)
sphingosine
liver transplant
Grafts
Liver
Liver Transplantation
Rats
phosphotransferases (kinases)
inflammation
Inflammation
Transplants
Infiltration
chemokines
liver
Macrophages
rats
Wounds and Injuries
Transplantation
Chemokines
macrophages

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Liu, Q., Rehman, H., Shi, Y., Krishnasamy, Y., Lemasters, J. J., Smith, C., & Zhong, Z. (2012). Inhibition of sphingosine kinase-2 suppresses inflammation and attenuates graft injury after liver transplantation in rats. PloS one, 7(7), [e41834]. https://doi.org/10.1371/journal.pone.0041834
Liu, Qinlong ; Rehman, Hasibur ; Shi, Yanjun ; Krishnasamy, Yasodha ; Lemasters, John J. ; Smith, Charles ; Zhong, Zhi. / Inhibition of sphingosine kinase-2 suppresses inflammation and attenuates graft injury after liver transplantation in rats. In: PloS one. 2012 ; Vol. 7, No. 7.
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abstract = "Inflammation mediates/promotes graft injury after liver transplantation (LT). This study investigated the roles of sphingosine kinase-2 (SK2) in inflammation after LT. Liver grafts were stored in UW solution with and without ABC294640 (100 μM), a selective inhibitor of SK2, before implantation. Hepatic sphingosine-1-phosphate (S1P) levels increased ~4-fold after LT, which was blunted by 40{\%} by ABC294640. Hepatic toll-like receptor-4 (TLR4) expression and nuclear factor-κB (NF-κB) p65 subunit phosphorylation elevated substantially after transplantation. The pro-inflammatory cytokines/chemokines tumor necrosis factor-α, interleukin-1β and C-X-C motif chemokine 10 mRNAs increased 5.9-fold, 6.1-fold and 16-fold, respectively following transplantation, while intrahepatic adhesion molecule-1 increased 5.7-fold and monocytes/macrophage and neutrophil infiltration and expansion of residential macrophage population increased 7.8-13.4 fold, indicating enhanced inflammation. CD4+ T cell infiltration and interferon-γ production also increased. ABC294640 blunted TLR4 expression by 60{\%}, NF-κB activation by 84{\%}, proinflammatory cytokine/chemokine production by 45-72{\%}, adhesion molecule expression by 54{\%} and infiltration of monocytes/macrophages and neutrophils by 62-67{\%}. ABC294640 also largely blocked CD4+ T cell infiltration and interferon-γ production. Focal necrosis and apoptosis occurred after transplantation with serum alanine aminotransferase (ALT) reaching ~6000 U/L and serum total bilirubin elevating to ~1.5 mg/dL. Inhibition of SK2 by ABC294640 blunted necrosis by 57{\%}, apoptosis by 74{\%}, ALT release by ~68{\%}, and hyperbilirubinemia by 74{\%}. Most importantly, ABC294640 also increased survival from ~25{\%} to ~85{\%}. In conclusion, SK2 plays an important role in hepatic inflammation responses and graft injury after cold storage/transplantation and represents a new therapeutic target for liver graft failure.",
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Inhibition of sphingosine kinase-2 suppresses inflammation and attenuates graft injury after liver transplantation in rats. / Liu, Qinlong; Rehman, Hasibur; Shi, Yanjun; Krishnasamy, Yasodha; Lemasters, John J.; Smith, Charles; Zhong, Zhi.

In: PloS one, Vol. 7, No. 7, e41834, 25.07.2012.

Research output: Contribution to journalArticle

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T1 - Inhibition of sphingosine kinase-2 suppresses inflammation and attenuates graft injury after liver transplantation in rats

AU - Liu, Qinlong

AU - Rehman, Hasibur

AU - Shi, Yanjun

AU - Krishnasamy, Yasodha

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AU - Smith, Charles

AU - Zhong, Zhi

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