Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, EA 4331, Université de Poitiers, Poitiers, France.
Eur Cytokine Netw. 2009 Sep;20(3):101-7. doi: 10.1684/ecn.2009.0163.
The mevalonate kinase deficiency (MKD), including hyperimmunoglobulinemia D periodic fever syndrome (HIDS) and the more severe mevalonic aciduria are rare, autosomal recessive, autoinflammatory diseases belonging to the hereditary periodic fever (HPF) family. Other members include: familial mediterranean fever (FMF), the cryopyrin-associated periodic syndromes (CAPS) and TNFR-associated periodic syndromes (TRAPS). MKD is caused by mutations in the gene encoding mevalonate kinase (MK), an enzyme of the cholesterol pathway, leading to its inactivation. The molecular mechanisms linking MKD and abnormalities of isoprenoid biosynthesis to cytokine production and inflammation have yet to be fully elucidated. Statins, which are extensively prescribed for lowering cholesterol, are potent inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, the enzyme directly upstream of MK. In this review, we discuss recent reports demonstrating that in vitro inhibition of the mevalonate pathway by statins specifically increases the production, by activated monocytes, of cytokines of the IL-1 family, by enhancing caspase-1 activity, the enzyme responsible for IL-1beta and IL-18 maturation. The molecular mechanisms involve geranylgeranylation and the enhancement of the activity of G proteins such as Rac-1. Interestingly, activated fibroblasts from MKD patients secrete more IL-1beta than fibroblasts from healthy donors. Taken together, these data highlight the specific enhancement of the IL-1 family of cytokines, the maturation of which is caspase-1-dependent in MKD. Finally, the spectacular decrease in febrile attacks in patients with severe HIDS under IL-1 receptor antagonist (anakinra) treatment, reinforces this hypothesis. Deregulated caspase-1 activation could be responsible for the inflammatory component of MKD, thereby mechanistically linking MKD to FMF and CAPS through cytokines of the IL-1 family.
Mevalonate kinase deficiency (MKD), including hyperimmunoglobulinemia D periodic fever syndrome (HIDS) and the more severe mevalonic aciduria, are rare, autosomal recessive, autoinflammatory diseases belonging to the hereditary periodic fever (HPF) family. Other members include: familial mediterranean fever (FMF), the cryopyrin-associated periodic syndromes (CAPS) and TNFR-associated periodic syndromes (TRAPS). MKD is caused by mutations in the gene encoding mevalonate kinase (MK), an enzyme of the cholesterol pathway, leading to its inactivation. The molecular mechanisms linking MKD and abnormalities of isoprenoid biosynthesis to cytokine production and inflammation have yet to be fully elucidated. Statins, which are extensively prescribed for lowering cholesterol, are potent inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, the enzyme directly upstream of MK. In this review, we discuss recent reports demonstrating that in vitro inhibition of the mevalonate pathway by statins specifically increases the production, by activated monocytes, of cytokines of the IL-1 family, by enhancing caspase-1 activity, the enzyme responsible for IL-1beta and IL-18 maturation. The molecular mechanisms involve geranylgeranylation and the enhancement of the activity of G proteins such as Rac-1. Interestingly, activated fibroblasts from MKD patients secrete more IL-1beta than fibroblasts from healthy donors. Taken together, these data highlight the specific enhancement of the IL-1 family of cytokines, the maturation of which is caspase-1-dependent in MKD. Finally, the spectacular decrease in febrile attacks in patients with severe HIDS under IL-1 receptor antagonist (anakinra) treatment, reinforces this hypothesis. Deregulated caspase-1 activation could be responsible for the inflammatory component of MKD, thereby mechanistically linking MKD to FMF and CAPS through cytokines of the IL-1 family.
Mevalonate 激酶缺乏症（MKD），包括高免疫球蛋白 D 周期性发热综合征（HIDS）和更严重的异戊酸血症，是罕见的常染色体隐性自身炎症性疾病，属于遗传性周期性发热（HPF）家族。其他成员包括家族性地中海热（FMF）、冷球蛋白血症相关周期性综合征（CAPS）和肿瘤坏死因子受体相关周期性综合征（TRAPS）。MKD 是由编码 Mevalonate 激酶（MK）的基因突变引起的，MK 是胆固醇途径中的一种酶，导致其失活。将 MKD 与异戊烯醇生物合成异常与细胞因子产生和炎症联系起来的分子机制尚未完全阐明。他汀类药物被广泛用于降低胆固醇，是 3-羟基-3-甲基戊二酰辅酶 A 还原酶（MK 的直接上游酶）的有效抑制剂。在这篇综述中，我们讨论了最近的报道，这些报道表明他汀类药物体外抑制 Mevalonate 途径会特异性增加激活单核细胞产生白细胞介素-1 家族细胞因子的能力，通过增强半胱天冬酶-1（负责白细胞介素-1β和白细胞介素-18 成熟的酶）的活性。分子机制涉及法尼基化和 G 蛋白（如 Rac-1）活性的增强。有趣的是，MKD 患者的激活成纤维细胞比健康供体的成纤维细胞分泌更多的白细胞介素-1β。总之，这些数据突出了白细胞介素-1 家族细胞因子的特异性增强，在 MKD 中，其成熟依赖于半胱天冬酶-1。最后，在严重 HIDS 患者中，白细胞介素-1 受体拮抗剂（阿那白滞素）治疗可显著减少发热发作，这进一步证实了这一假说。失调的半胱天冬酶-1 激活可能是 MKD 炎症成分的原因，从而通过白细胞介素-1 家族的细胞因子将 MKD 与 FMF 和 CAPS 在机制上联系起来。
