Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Inflamm Bowel Dis. 2010 Dec;16(12):2022-33. doi: 10.1002/ibd.21318.
Tacrolimus is a novel immunomodulator for inflammatory bowel diseases. Immunosuppressive effects of tacrolimus on T cells are well known; however, the effects of tacrolimus on macrophages remain unclear. The aim of this study was to investigate the effects of tacrolimus on activated macrophages and to examine its efficacy in murine colitis models.
Proinflammatory cytokine production from lipopolysaccharide (LPS)-stimulated peritoneal macrophages of IL-10-knockout (KO) mice with and without tacrolimus was measured. We investigated the effects of tacrolimus on nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and caspase activation in macrophages and the induction of apoptosis in macrophages in vitro and examined the in vivo apoptotic effect of tacrolimus on colonic macrophages in IL-10-KO mice. We evaluated the effect of the rectal administration of tacrolimus on colonic inflammation in IL-10-KO mice and dextran sulfate sodium (DSS)-induced colitis in CB.17/SCID mice.
Proinflammatory cytokine production from tacrolimus-treated macrophages was significantly lower than that from untreated cells. Tacrolimus suppressed LPS-induced activation of both NF-κB and MAPK in macrophages and induced apoptosis of macrophages via activation of caspases 3 and 9. Rectal administration of tacrolimus evoked apoptosis of colonic macrophages in IL-10-KO mice. Moreover, the rectal administration of tacrolimus ameliorated colitis in IL-10-KO mice and DSS-induced colitis in CB.17/SCID mice. Gene expression of inflammatory cytokines in colonic mucosa was significantly lower in tacrolimus-treated mice than in untreated mice.
Tacrolimus suppresses the function of activated macrophages and promotes their apoptosis, which may lead to the amelioration of colonic inflammation.
他克莫司是一种新型的免疫调节剂，可用于治疗炎症性肠病。其对 T 细胞的免疫抑制作用已得到广泛证实，但对巨噬细胞的作用尚不清楚。本研究旨在探讨他克莫司对活化巨噬细胞的作用，并观察其在小鼠结肠炎模型中的疗效。
采用 IL-10 基因敲除（KO）小鼠腹腔巨噬细胞，观察 LPS 刺激后有无他克莫司存在时促炎细胞因子的产生。我们研究了他克莫司对巨噬细胞中核因子-κB（NF-κB）、丝裂原活化蛋白激酶（MAPK）和半胱天冬酶激活的影响，以及他克莫司在体外诱导巨噬细胞凋亡的作用，并观察了他克莫司在 IL-10-KO 小鼠结肠巨噬细胞中的体内凋亡作用。我们评价了直肠给予他克莫司对 IL-10-KO 小鼠和葡聚糖硫酸钠（DSS）诱导的 CB.17/SCID 小鼠结肠炎的影响。
与未处理细胞相比，用他克莫司处理后的巨噬细胞促炎细胞因子的产生明显降低。他克莫司抑制了 LPS 诱导的巨噬细胞中 NF-κB 和 MAPK 的激活，并通过激活半胱天冬酶 3 和 9 诱导巨噬细胞凋亡。直肠给予他克莫司可引起 IL-10-KO 小鼠结肠巨噬细胞凋亡。此外，直肠给予他克莫司可改善 IL-10-KO 小鼠的结肠炎和 DSS 诱导的 CB.17/SCID 小鼠结肠炎。与未处理组相比，他克莫司治疗组小鼠结肠黏膜炎性细胞因子的基因表达明显降低。
他克莫司抑制活化巨噬细胞的功能，促进其凋亡，从而可能改善结肠炎症。
