Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis

Michael J. Pulkoski-Gross, Joachim D. Uys, K. Alexa Orr-Gandy, Nicolas Coant, Agnieszka B. Bialkowska, Zdzislaw M. Szulc, Aiping Bai, Alicja Bielawska, Danyelle M. Townsend, Yusuf A. Hannun, Lina M. Obeid, Ashley J. Snider

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid metabolite which has been implicated in many diseases including cancer and inflammatory diseases. Recently, sphingosine kinase 1 (SK1), one of the isozymes which generates S1P, has been implicated in the development and progression of inflammatory bowel disease (IBD). Based on our previous work, we set out to determine the efficacy of a novel SK1 selective inhibitor, LCL351, in a murine model of IBD. LCL351 selectively inhibits SK1 both in vitro and in cells. LCL351, which accumulates in relevant tissues such as colon, did not have any adverse side effects in vivo. In mice challenged with dextran sodium sulfate (DSS), a murine model for IBD, LCL351 treatment protected from blood loss and splenomegaly. Additionally, LCL351 treatment reduced the expression of pro-inflammatory markers, and reduced neutrophil infiltration in colon tissue. Our results suggest inflammation associated with IBD can be targeted pharmacologically through the inhibition and degradation of SK1. Furthermore, our data also identifies desirable properties of SK1 inhibitors.

Original languageEnglish (US)
Pages (from-to)47-56
Number of pages10
JournalProstaglandins and Other Lipid Mediators
Volume130
DOIs
StatePublished - May 1 2017
Externally publishedYes

Keywords

  • Inflammation
  • Inflammatory Bowel Disease
  • Sphingolipids
  • Sphingosine 1-Phosphate
  • Sphingosine Kinase

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Pharmacology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis'. Together they form a unique fingerprint.

Cite this