Levels of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase are reduced in inflammatory bowel disease:: evidence for involvement of TNF-α
Levels of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase are reduced in inflammatory bowel disease:: evidence for involvement of TNF-α
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DOI：
10.1152/ajpgi.00348.2005
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发表时间：
2006-02-01
影响因子：
4.5
通讯作者：
Dannenberg, AJ
中科院分区：
文献类型：
--
作者：
Otani, T;Yamaguchi, K;Dannenberg, AJ
在炎症性肠病（IBD）患者的炎症粘膜中检测到PGE（2）含量增加。这种增加归因于PGE的合成增强而不是催化剂减少（2）。15-羟基前列腺素脱氢酶（15-PGDH）在PGE的催化中起主要作用（2）。在这项研究中，我们调查了IBD患者的炎症粘膜中15-PGDH的量是否改变。克罗恩病和溃疡性结肠炎患者的炎症粘膜中15-PGDH蛋白和mRNA的量显著减少。原位杂交结果表明，15-PGDH在正常结肠上皮中表达，但在IBD患者的炎症结肠粘膜中几乎不表达。由于TNF-α在IBD中的重要性，我们还确定了TNF-α对体外15-PGDH表达的影响。用TNF-α处理抑制了人结肠细胞中15-PGDH的转录，导致15-PGDH mRNA和蛋白质以及酶活性的量减少。相比之下，TNF-α诱导两种酶（环氧合酶-2和微粒体前列腺素E合酶-1），有助于增加PGE的合成（2）。过表达15-PGDH阻断了TNF-α介导的PGE（2）产生的增加。综上所述，这些结果表明，15-PGDH的表达减少有助于IBD患者炎症粘膜中发现的PGE（2）水平升高。炎症粘膜中15-PGDH含量的减少至少部分可以通过TNF-α介导的15-PGDH转录抑制来解释。
Increased amounts of PGE(2) have been detected in the inflamed mucosa of patients with inflammatory bowel disease (IBD). This increase has been attributed to enhanced synthesis rather than reduced catabolism of PGE(2). 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) plays a major role in the catabolism of PGE(2). In this study, we investigated whether amounts of 15-PGDH were altered in inflamed mucosa from patients with IBD. Amounts of 15-PGDH protein and mRNA were markedly reduced in inflamed mucosa from patients with Crohn's disease and ulcerative colitis. In situ hybridization demonstrated that 15-PGDH was expressed in normal colonic epithelium but was virtually absent in inflamed colonic mucosa from IBD patients. Because of the importance of TNF-alpha in IBD, we also determined the effects of TNF-alpha on the expression of 15-PGDH in vitro. Treatment with TNF-alpha suppressed the transcription of 15-PGDH in human colonocytes, resulting in reduced amounts of 15-PGDH mRNA and protein and enzyme activity. In contrast, TNF-alpha induced two enzymes (cyclooxygenase-2 and microsomal prostaglandin E synthase-1) that contribute to increased synthesis of PGE(2). Overexpressing 15-PGDH blocked the increase in PGE(2) production mediated by TNF-alpha. Taken together, these results suggest that reduced expression of 15-PGDH contributes to the elevated levels of PGE(2) found in inflamed mucosa of IBD patients. The decrease in amounts of 15-PGDH in inflamed mucosa can be explained at least, in part, by TNF-alpha-mediated suppression of 15-PGDH transcription.