Low-dose Warfarin Functions as an Immunomodulator to Prevent Cyclophosphamide-induced NOD Diabetes

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Warfarin has been used as an anticoagulant for a long time. Recently, thepleiotropic effect of warfarin has been investigated. As low-dose warfarin has beenreported to have anti-inflammatory effect through suppression of IL-6 secretion andinhibit the immune-associated signal between Tyro3 and its ligand, Gas6, the effect oflow-dose warfarin on autoimmune diabetes in NOD mice was examined. To investigatethe anti-inflammatory effect of warfarin, IL-6 secretion by splenocytes was examined inthe presence of various concentrations of warfarin. Low concentration of warfarininhibited IL-6 secretion. mRNA expression of Rse, one of the Tyro3 receptor familymembers, and Gas6 were analyzed in NOD mice. It was detected in islets, splenocytesand bone-marrow derived dendritic cells. 0.25 mg/l or 0.50 mg/l of warfarin was orallyadministered to NOD mice as a cyclophosphamide-induced diabetes model. Oraladministration of warfarin at much lower doses than those clinically used as ananticoagulant significantly reduced the degree of insulitis and diabetes incidence in thismodel. We previously demonstrated that anti-FasL Ab-treatment led to completeprevention of autoimmune diabetes in NOD mice. As Fas/FasL signaling is reported tobe essential for cyclophosphamide-induced diabetes model, we extracted RNA fromlymphocytes of the inguinal lymph nodes of anti-FasL Ab-treated NOD mice andperformed real-time PCR to determine expression of Rse gene. Interestingly, theexpression of Rse gene related to the blockade of Fas/FasL signaling was reduced to lessthan half the level of untreated mice. In conclusion, low-dose warfarin is a potentialimmunomodulator which can prevent autoimmune diabetes.
神戸大学の論文

Low-dose Warfarin Functions as an Immunomodulator to Prevent Cyclophosphamide-induced NOD Diabetes

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