The prostaglandin D₂ metabolite, 15-deoxy-Δ^12,14-Prostaglandin J₂ (15d-PGJ₂), exerts an anti-inflammatory effect through peroxisome proliferator-activated receptor γ (PPARγ)-dependent and -independent anti-inflammatory actions. In the present study, we focused on heme oxygenase-1 (HO-1) induced by 15d-PGJ₂, and evaluated the effects of enema treatment with 15d-PGJ₂ in the development of intestinal inflammation using a murine colitis model. Acute colitis was induced with dextran sulfate sodium (DSS) in male C57BL/6 mice (8 weeks old) and NF-E2-related factor-2 (Nrf2) deficient mice. Mice were rectally administered 15d-PGJ₂ (1 μM, 0.2 mL: 66.9 ng) daily during DSS administration. Intestinal expression of HO-1 mRNA and protein after rectal administration of 15d-PGJ₂ was evaluated by real-time PCR and western blotting, respectively. A disease activity index (DAI) was determined on a daily basis for each animal, and consisted of a calculated score based on changes in body weight, stool consistency, and intestinal bleeding. Tissue-associated myeloperoxidase (MPO) activity as an index of neutrophil infiltration and mRNA expression levels of TNF-α, IFN-γ, and IL-17A were measured in the colonic mucosa. In addition, we evaluated the effects of co-treatment with a HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), or a specific PPARγ antagonist, GW9662. As a result, rectal administration of 15d-PGJ₂ markedly induced HO-1 protein and mRNA expression in the colonic mucosa. Treatment with 15d-PGJ₂ ameliorated the increase in DAI score and MPO activity and the mRNA expression levels of TNF-α, IFN-γ, and IL-17A after DSS administration. These effects of 15d-PGJ₂ against intestinal inflammation were negated by co-treatment with ZnPP, but not with GW9662. In Nrf2 deficient mice, the rectal administration of 15d-PGJ₂ did not affect colonic HO-1 expression and activity of DSS-induced colitis. These results demonstrate that 15d-PGJ₂ inhibits development of intestinal inflammation in mice via PPAR-independent and Nrf2-HO-1-dependent mechanisms.

前列腺素d ₂代谢物，15-脱氧Δ ^12,14 -前列腺素Ĵ ₂（15D-PGJ ₂），通过施加过氧化物酶体增殖物激活受体γ（PPARγ） -依赖性和非依赖性抗炎作用的抗炎作用。在本研究中，我们集中于15d-PGJ ₂诱导的血红素加氧酶-1（HO-1），并使用鼠结肠炎模型评估了15d-PGJ ₂灌肠治疗在肠道炎症发展中的作用。在雄性C57BL / 6小鼠（8周龄）和NF-E2相关因子2（Nrf2）缺陷小鼠中，用右旋糖酐硫酸钠（DSS）诱发急性结肠炎。小鼠经直肠给予15d-PGJ ₂DSS给药期间每天（1μM，0.2 mL：66.9 ng）。直肠给药15d-PGJ ₂后，分别通过实时荧光定量PCR和Western blotting评估HO-1 mRNA和蛋白在肠道中的表达。每天确定每只动物的疾病活动指数（DAI），并由基于体重，粪便稠度和肠道出血变化的计算得分组成。组织相关的髓过氧化物酶（MPO）活性作为嗜中性粒细胞浸润的指标，并测量了结肠粘膜中TNF-α，IFN-γ和IL-17A的mRNA表达水平。此外，我们评估了与HO-1抑制剂，原卟啉锌IX（ZnPP）或特定的PPARγ拮抗剂GW9662共同治疗的效果。结果，直肠给药15d-PGJ ₂在结肠粘膜中明显诱导HO-1蛋白和mRNA表达。给予DSS后，用15d-PGJ _2处理可改善DAI评分和MPO活性以及TNF-α，IFN-γ和IL-17A的mRNA表达水平。15d-PGJ ₂抗肠道炎症的这些作用通过与ZnPP共同治疗而未与GW9662共同治疗而被否定。在缺乏Nrf2的小鼠中，直肠给药15d-PGJ ₂不会影响结肠HO-1的表达和DSS诱导的结肠炎的活性。这些结果表明15d-PGJ ₂通过非PPAR和Nrf2-HO-1依赖性机制抑制小鼠肠道炎症的发展。