Melatonin inhibits the sphingosine kinase 1/sphingosine-1-phosphate signaling pathway in rabbits with fulminant hepatitis of viral origin.
The sphingosine kinase (SphK)1/sphingosine-1-phosphate (S1P) pathway is involved in multiple biological processes, including liver diseases. This study investigate whether modulation of the SphK1/S1P system associates to the beneficial effects of melatonin in an animal model of acute liver failure (ALF) induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2 × 10(4) hemagglutination units of a RHDV isolate and received 20 mg/kg of melatonin at 0, 12, and 24 hr postinfection. Liver mRNA levels, protein concentration, and immunohistochemical labeling for SphK1 increased in RHDV-infected rabbits. S1P production and protein expression of the S1PR1 receptor were significantly elevated following RHDV infection. These effects were significantly reduced by melatonin. Rabbits also exhibited increased expression of toll-like receptor (TLR)4, tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, nuclear factor-kappa B (NF-κB) p50 and p65 subunits, and phosphorylated inhibitor of kappa B (IκB)α. Melatonin administration significantly inhibited those changes and induced a decreased immunoreactivity for RHDV viral VP60 antigen in the liver. Results obtained indicate that the SphK1/S1P system activates in parallel to viral replication and the inflammatory process induced by the virus. Inhibition of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in this animal model of ALF, and supports the potential of melatonin as an antiviral agent.
Institute of Biomedicine (IBIOMED), University of León, León, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
Irene
I
Crespo
Institute of Biomedicine (IBIOMED), University of León, León, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
Beatriz
B
San-Miguel
Institute of Biomedicine (IBIOMED), University of León, León, Spain.
Diana I
DI
Sánchez
Institute of Biomedicine (IBIOMED), University of León, León, Spain.
Bárbara
B
González-Fernández
Department of Animal Health, University of León, León, Spain.
Marcelino
M
Álvarez
Institute of Biomedicine (IBIOMED), University of León, León, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
Javier
J
González-Gallego
Institute of Biomedicine (IBIOMED), University of León, León, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
María J
MJ
Tuñón
D000818:Animals; D017250:Caliciviridae Infections / Q000188:drug therapy / Q000378:metabolism*; D017929:Hemorrhagic Disease Virus, Rabbit; D006524:Hepatitis, Viral, Animal / Q000188:drug therapy / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000188:drug therapy / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D008550:Melatonin / Q000493:pharmacokinetics*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
D008246:Lysophospholipids; D008550:Melatonin; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
acute liver failure; liver; melatonin; sphingosine kinase 1; sphingosine-1-phosphate