Department of Immunology, Graduate School of Medicine, Ehime University, 454 Shitsukawa, Toon-shi, Ehime, 791-0295, Japan; Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan.
Department of Immunology, Graduate School of Medicine, Ehime University, 454 Shitsukawa, Toon-shi, Ehime, 791-0295, Japan.
Biochem Biophys Res Commun. 2020 Sep 17;530(2):355-361. doi: 10.1016/j.bbrc.2020.08.009. Epub 2020 Aug 13.
Th2 cytokine such as IL-4, IL -5 and IL-13 are important therapeutic targets for Th2-type chronic inflammation. Several biologics targeting Th2 cytokine and its receptors are effective in clinical practice; however, the development of small-molecule compounds that inhibit Th2 cytokine productions is awaited. We found that an inhibitor for pyruvate dehydrogenase kinase (PDHK) suppresses the differentiation of IL-5/IL-13-producing Th2 cells. The expression of the Th2-related transcriptional factors Pparγ was decreased by treatment with inhibitor, whereas Gata3, a master regulator of Th2 cell differentiation, remained unchanged. The oxygen consumption rate was unaffected, whereas the level of farnesylated proteins was decreased by the PDHK inhibitor. Furthermore, the inhibitors for farnesyltransferase and hydroxymethylglutaryl-CoA reductase showed an inhibitory effect similar to that of the PDHK inhibitor. These results suggest that the mevalonate biosynthesis and subsequent protein prenylation may be novel therapeutic target for Th2 cell-dependent immune dysregulation, such as in allergic diseases.
2 型细胞因子，如 IL-4、IL-5 和 IL-13，是 2 型慢性炎症的重要治疗靶点。几种针对 2 型细胞因子及其受体的生物制剂在临床实践中有效；然而，抑制 2 型细胞因子产生的小分子化合物的开发仍在等待中。我们发现，丙酮酸脱氢酶激酶（PDHK）抑制剂可抑制产生 IL-5/IL-13 的 Th2 细胞的分化。抑制剂处理降低了 Th2 相关转录因子 Pparγ 的表达，而 Th2 细胞分化的主调控因子 Gata3 则保持不变。PDHK 抑制剂不影响耗氧量，但降低法尼基化蛋白水平。此外，法尼基转移酶和羟甲基戊二酰辅酶 A 还原酶抑制剂也显示出类似于 PDHK 抑制剂的抑制作用。这些结果表明，甲羟戊酸生物合成和随后的蛋白异戊二烯化可能是治疗 2 型细胞依赖性免疫失调的新靶点，如过敏疾病。
