TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells
TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells
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DOI：
10.4049/immunohorizons.2000007
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发表时间：
2020-03
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通讯作者：
Hai The Phung;H. Nagashima;Shuhei Kobayashi;N. Asano;Tomoaki Machiyama;Tsuyoshi Sakurai;Shunichi Tayama;A. Asao;A. Imatani;T. Kawabe;Y. Okuyama;N. Ishii;T. So
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作者：
Hai The Phung;H. Nagashima;Shuhei Kobayashi;N. Asano;Tomoaki Machiyama;Tsuyoshi Sakurai;Shunichi Tayama;A. Asao;A. Imatani;T. Kawabe;Y. Okuyama;N. Ishii;T. So
肿瘤坏死因子相关因子5（TRAF 5）是一种细胞溶质衔接蛋白，作为炎症调节因子发挥作用。然而，TRAF 5的体内功能仍不清楚，TRAF 5如何控制肠道炎症反应也尚不清楚。在这项研究中，我们发现Traf 5 −/−小鼠的肠上皮细胞表达的NF-κ B调节的促炎基因（如Tnf，Il 6和Cxcl 1）水平显著较低，早在葡聚糖硫酸钠（DSS）暴露后第3天，与野生型小鼠相比。DSS处理的Traf 5 −/−小鼠的肠道屏障完整性在这个早期时间点保持完整，Traf 5 −/−小鼠在稍后的时间点显示体重减轻和结肠长度延长。令人惊讶的是，在DSS后Traf 5 −/−小鼠的结肠组织中TRAF 2而不是TRAF 3的蛋白水平降低，表明TRAF 5对炎症结肠中TRAF 2蛋白稳定性的需求。骨髓嵌合体的实验证实，TRAF 5在非造血细胞的缺陷导致了衰减的结肠炎。我们的体外实验表明，促炎细胞因子以蛋白酶体依赖的方式显著促进Traf 5 −/−非造血细胞中TRAF 2蛋白的降解。总的来说，我们的数据表明TRAF 5在支持TRAF 2在非造血细胞中的促炎功能方面具有新的调节功能，这可能对肠道的急性炎症反应很重要。
TNFR-associated factor 5 (TRAF5) is a cytosolic adaptor protein and functions as an inflammatory regulator. However, the in vivo function of TRAF5 remains unclear, and how TRAF5 controls inflammatory responses in the intestine is not well understood. In this study, we found that intestinal epithelial cells from Traf5−/− mice expressed a significantly lower level of NF-κB–regulated proinflammatory genes, such as Tnf, Il6, and Cxcl1, as early as day 3 after dextran sulfate sodium (DSS) exposure when compared with wild-type mice. The intestinal barrier integrity of DSS-treated Traf5−/− mice remained intact at this early time point, and Traf5−/− mice showed decreased body weight loss and longer colon length at later time points. Surprisingly, the protein level of TRAF2, but not TRAF3, was reduced in colon tissues of Traf5−/− mice after DSS, indicating the requirement of TRAF5 for TRAF2 protein stability in the inflamed colon. Experiments with bone marrow chimeras confirmed that TRAF5 deficiency in nonhematopoietic cells caused the attenuated colitis. Our in vitro experiments demonstrated that proinflammatory cytokines significantly promoted the degradation of TRAF2 protein in Traf5−/− nonhematopoietic cells in a proteasome-dependent manner. Collectively, our data suggest a novel regulatory function of TRAF5 in supporting the proinflammatory function of TRAF2 in nonhematopoietic cells, which may be important for acute inflammatory responses in the intestine.