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Nitric oxide signaling mediates induction of sphingosine kinase caused by ceramide synthase inhibition
Author(s) -
Suzuki Hirofumi,
Sharma Raghubir P.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a697-d
Subject(s) - ceramide synthase , sphingosine , ceramide , sphingolipid , nitric oxide synthase , sphingosine kinase , nitric oxide , chemistry , lipid signaling , sphingosine kinase 1 , signal transduction , tumor necrosis factor alpha , biochemistry , kinase , proinflammatory cytokine , biology , sphingosine 1 phosphate , microbiology and biotechnology , apoptosis , enzyme , inflammation , immunology , receptor , organic chemistry
Free sphingoid bases and their metabolites are important messengers involved in signal transduction leading to either cell survival or death. Sphingosine and its congener dihydrosphingosine (sphinganine) are known apoptotic molecules whereas their respective 1‐phosphates are protective. The equilibrium between sphingoid bases and their phosphates is maintained by sphingosine kinase (SK). We previously reported SK induction along with the increase of serine palmitoyltransferase (SPT) after ceramide synthase inhibition by fumonisin B 1 (FB), a natural mycotoxin that prevents incorporation of free sphingoid bases into ceramide leading to cellular accumulation of sphinganine and sphingosine. FB also caused inducible nitric oxide synthase (iNOS) induction. In the current study we employed iNOS knockout (KO) mice to evaluate the role of nitric oxide (NO) on FB‐induced SK modulation. The iNOS‐KO mice exhibited increased hepatotoxicity after FB treatment compared to wild type counterparts, accompanied by a lack of SK induction. The FB‐induced SPT was unaffected. Deletion of iNOS gene did not prevent FB‐dependent induction of inflammatory cytokines, namely tumor necrosis factor α (TNFα), interferon γ and interleukin‐12. We therefore conclude that FB‐induced TNFα is responsible for iNOS induction that modulates SK activity; the lack of iNOS prevents sphingosine 1‐phosphate generation and deprives cells from its protective effects. (Supported in part by NIH ES09403)