Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis.
Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis.
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DOI：
10.4049/jimmunol.1501080
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发表时间：
2016-01-15
期刊：
影响因子：
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通讯作者：
Sheldon IM
中科院分区：
文献类型：
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作者：
Healey GD;Collier C;Griffin S;Schuberth HJ;Sandra O;Smith DG;Mahan S;Dieuzy-Labaye I;Sheldon IM
代谢变化可以影响对细菌的炎症反应。为了研究甲羟戊酸途径的局部操作是否会影响先天免疫，我们利用了一种独特的粘膜疾病模型——子宫内膜炎，其中炎症是先天免疫的结果。在牛子宫内膜细胞和器官培养中，IL对致病菌和LPS的反应被靶向甲羟戊酸途径的小分子调节。用多种他汀类药物、双膦酸盐、角鲨烯合成酶抑制剂和小干扰RNA治疗表明，抑制法尼基-二磷酸法尼基转移酶（角鲨烯合成酶），但不抑制3-羟基-3-甲基戊二酰辅酶a还原酶或法尼基二磷酸合成酶，降低了子宫内膜器官和细胞对致病菌和LPS的炎症反应。虽然甲羟戊酸途径的操作降低了细胞胆固醇，但对炎症的影响与胆固醇浓度无关，因为使用环糊精消耗胆固醇并没有改变炎症反应。用类异戊二烯甲戊酸途径中间体，二磷酸法尼酯和二磷酸香叶基香叶基治疗，也减少了子宫内膜细胞对LPS的炎症反应。这些数据表明，操纵甲羟戊酸途径调节子宫内膜内的先天免疫，而类异戊二烯是这一过程中的调节分子，这些知识可以用于开发新的治疗策略。
Metabolic changes can influence inflammatory responses to bacteria. To examine whether localized manipulation of the mevalonate pathway impacts innate immunity, we exploited a unique mucosal disease model, endometritis, where inflammation is a consequence of innate immunity. IL responses to pathogenic bacteria and LPS were modulated in bovine endometrial cell and organ cultures by small molecules that target the mevalonate pathway. Treatment with multiple statins, bisphosphonates, squalene synthase inhibitors, and small interfering RNA showed that inhibition of farnesyl-diphosphate farnesyl transferase (squalene synthase), but not 3-hydroxy-3-methylglutaryl-CoA reductase or farnesyl diphosphate synthase, reduced endometrial organ and cellular inflammatory responses to pathogenic bacteria and LPS. Although manipulation of the mevalonate pathway reduced cellular cholesterol, impacts on inflammation were independent of cholesterol concentration as cholesterol depletion using cyclodextrins did not alter inflammatory responses. Treatment with the isoprenoid mevalonate pathway-intermediates, farnesyl diphosphate and geranylgeranyl diphosphate, also reduced endometrial cellular inflammatory responses to LPS. These data imply that manipulating the mevalonate pathway regulates innate immunity within the endometrium, and that isoprenoids are regulatory molecules in this process, knowledge that could be exploited for novel therapeutic strategies.