Journal
INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY
Volume 35, Issue -, Pages -Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/20587384211053274
Keywords
sphingosine kinase 1; sphingosine kinase 2; immune-mediated hepatitis; sphingolipids
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Sphingosine kinase 1 (SphK1) inhibitor alleviated liver damage and inflammation in a murine model of immune-mediated hepatitis, leading to a reduction in serum IFN-gamma levels. The study suggests a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, highlighting the potential of isoenzyme-directed therapies.
Background: Sphingosine kinase has been identified as playing a central role in the immune cascade, being a common mediator in the cellular response to a variety of signals. The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characterized. Aim: To determine the different roles played by SphK1 and SphK2 in the regulation of immune-mediated disorders. Methods: Nine groups of mice were studied. Concanavalin A (ConA) injection was used to induce immune-mediated hepatitis. Mice were treated with SphK1 inhibitor (termed SphK-I) and SphK2 inhibitor (termed ABC294640), prior to ConA injection, and effects of treatment on liver enzymes, subsets of T lymphocytes, and serum levels of cytokines were observed. Results: While liver enzyme elevation was ameliorated by administration of SphK1 inhibitor, SphK2 inhibitor-treated mice did not show this tendency. A marked decrease in expression of CD25(+) T-cells and Foxp+ T-cells was observed in mice treated with a high dose of SphK1 inhibitor. Alleviation of liver damage was associated with a statistically significant reduction of serum IFN gamma levels in mice treated with SphK1 inhibitor and not in those treated with SphK2 inhibitor. Conclusions: Early administration of SphK1 inhibitor in a murine model of immune-mediated hepatitis alleviated liver damage and inflammation with a statistically significant reduction in IFN-gamma levels. The data support a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, and suggests that isoenzyme-directed therapies can improve the effect of targeting these pathways.
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