title: Low-dose warfarin functions as an immunomodulator to prevent cyclophosphamide-induced NOD diabetes.
abstract: Warfarin has been used as an anticoagulant for a long time. Recently, the pleiotropic effect of warfarin has been investigated. As low-dose warfarin has been reported to have anti-inflammatory effect through suppression of IL-6 secretion and inhibit the immune-associated signal between Tyro3 and its ligand, Gas6, the effect of low-dose warfarin on autoimmune diabetes in NOD mice was examined. To investigate the anti-inflammatory effect of warfarin, IL-6 secretion by splenocytes was examined in the presence of various concentrations of warfarin. Low concentration of warfarin inhibited IL-6 secretion. mRNA expression of Rse, one of the Tyro3 receptor family members, and Gas6 were analyzed in NOD mice. It was detected in islets, splenocytes and bone-marrow derived dendritic cells. 0.25 mg/l or 0.50 mg/l of warfarin was orally administered to NOD mice as a cyclophosphamide-induced diabetes model. Oral administration of warfarin at much lower doses than those clinically used as an anticoagulant significantly reduced the degree of insulitis and diabetes incidence in this model. We previously demonstrated that anti-FasL Ab-treatment led to complete prevention of autoimmune diabetes in NOD mice. As Fas/FasL signaling is reported to be essential for cyclophosphamide-induced diabetes model, we extracted RNA from lymphocytes of the inguinal lymph nodes of anti-FasL Ab-treated NOD mice and performed real-time PCR to determine expression of Rse gene. Interestingly, the expression of Rse gene related to the blockade of Fas/FasL signaling was reduced to less than half the level of untreated mice. In conclusion, low-dose warfarin is a potential immunomodulator which can prevent autoimmune diabetes.
authors.affiliation: Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Kurohara
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yasuda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Moriyama
authors.forename: Maki
authors.initials: M
authors.lastname: Nakayama
authors.forename: Muneaki
authors.initials: M
authors.lastname: Sakata
authors.forename: Katsumi
authors.initials: K
authors.lastname: Yamada
authors.forename: Reiko
authors.initials: R
authors.lastname: Kotani
authors.forename: Kenta
authors.initials: K
authors.lastname: Hara
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokono
authors.forename: Masao
authors.initials: M
authors.lastname: Nagata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014859:Warfarin / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D003520:Cyclophosphamide; D053222:Fas Ligand Protein; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D020794:Receptor Protein-Tyrosine Kinases; D014859:Warfarin; D019014:fas Receptor; D000099255:Growth Arrest-Specific Protein 6; C513478:Tyro3 protein, mouse