Journal
PROSTAGLANDINS & OTHER LIPID MEDIATORS
Volume 130, Issue -, Pages 47-56Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.prostaglandins.2017.03.006
Keywords
Inflammation; Sphingosine 1-Phosphate; Sphingosine Kinase; Sphingolipids; Inflammatory Bowel Disease
Categories
Funding
- Department of Veterans Affairs
- National Research Service Award NIH-NCI [F31 CA196315]
- Sphingolipid Animal Cancer Pathobiology Shared Resource Core [P01CA097132]
- Analytical Biochemistry Core [C06 RR015455, R56 ES017453]
- NIH-NIGMS [P30 GM103342]
- [P30 CA138313]
- [P20 RR017677]
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Sphingosine-l-phosphate (SIP) 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 SIT, 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 SKI. 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.
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