RESUMO
BACKGROUND: Spermidine suppress oxidative stress and is involved in various disease pathogenesis including ulcerative colitis (UC). Arginase 2 (ARG2) plays a central role in the synthesis of spermidine. This study aimed to clarify the effect of endogenously produced spermidine on colitis. METHODS: The physiological role of ARG2 and spermidine was investigated using Arg2-deficient mice with reduced spermidine. Immunohistochemical staining of the rectum was used to analyze ARG2 expression and spermidine levels in healthy controls and UC patients. RESULTS: In mice with dextran sulfate sodium-induced colitis, ARG2 and spermidine levels were increased in the rectal epithelium. Spermidine protects colonic epithelial cells from oxidative stress and Arg2 knockdown cells reduced antioxidant activity. Organoids cultured from the small intestine and colon of Arg2-deficient mice both were more susceptible to oxidative stress. Colitis was exacerbated in Arg2-deficient mice compared to wild-type mice. Supplementation with spermidine result in comparable severity of colitis in both wild-type and Arg2-deficient mice. In the active phase of UC, rectal ARG2 expression and spermidine accumulation were increased compared to remission. ARG2 and spermidine levels were similar in healthy controls and UC remission patients. CONCLUSIONS: ARG2 produces spermidine endogenously in the intestinal epithelium and has a palliative effect on ulcerative colitis. ARG2 and spermidine are potential novel therapeutic targets for UC.
Assuntos
Antioxidantes , Arginase , Colite Ulcerativa , Sulfato de Dextrana , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Espermidina , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Animais , Espermidina/farmacologia , Espermidina/metabolismo , Humanos , Camundongos , Antioxidantes/farmacologia , Arginase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Masculino , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Camundongos Knockout , Modelos Animais de Doenças , Feminino , Colo/metabolismo , Colo/patologia , Colo/efeitos dos fármacos , Pessoa de Meia-Idade , AdultoRESUMO
A 19-year-old woman, who had been receiving hormone replacement therapy for 13 months before the diagnosis of mosaic Turner syndrome (46XXp-/45X), developed Crohn's colitis and erythema nodosum of the lower legs. Colonoscopy revealed an anal fistula and the presence of deep longitudinal ulcers with cobblestoning in the colorectum. Therapy with prednisolone and adalimumab was effective for the intestinal and skin lesions. To date, all seven case reports of Turner syndrome in Japan have also developed Crohn's disease after hormone therapy, suggesting a possible association of sex hormones in the pathogenesis.