Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Mich., USA.
Pharmacology. 2012;89(3-4):117-26. doi: 10.1159/000336335. Epub 2012 Mar 7.
The proteasome is a multi-subunit complex that proteolytically cleaves proteins. The replacement of the constitutive proteasome subunits β1, β2, and/or β5 with the IFNγ-inducible subunits LMP2, MECL1, and/or LMP7 results in the 'immunoproteasome'. The inducible subunits change the cleavage specificities of the proteasome, but it is unclear whether they have functions in addition to this. The purpose of the present study was to determine the role of the proteasome in general, as well as LMP7 and MECL1 specifically, with regard to cytokine production by activated primary splenocytes.
A LMP7/MECL1-null mouse was engineered to determine the roles of these subunits in cytokine production. Isolated splenocytes from wild-type and LMP7/MECL1-/- mice were treated with lactacystin and activated with PMA and ionomycin and subsequently cytokine mRNA levels were quantified.
The present study demonstrates that LMP7/MECL1 regulates the expression of IFNγ, IL4, IL10, IL2Rβ, GATA3, and t-bet. In contrast, the regulation of IL2, IL13, TNFα, and IL2Rα by the proteasome appears to occur independently of LMP7/MECL1.
Collectively, the present study demonstrates that LMP7 and MECL1 regulate cytokine expression, suggesting this system represents a novel mechanism for the regulation of cytokines and cytokine signaling.
蛋白酶体是一种多亚基复合物，可对蛋白质进行蛋白水解切割。用 IFNγ 诱导的亚基 LMP2、MECL1 和/或 LMP7 替换组成型蛋白酶体亚基 β1、β2 和/或 β5，会产生“免疫蛋白酶体”。诱导型亚基改变了蛋白酶体的切割特异性，但尚不清楚它们除了这种作用之外是否还有其他功能。本研究旨在确定蛋白酶体以及 LMP7 和 MECL1 在激活的原代脾细胞细胞因子产生中的作用。
构建了 LMP7/MECL1 缺失小鼠，以确定这些亚基在细胞因子产生中的作用。从野生型和 LMP7/MECL1-/-小鼠中分离脾细胞，用 lactacystin 处理并用 PMA 和离子霉素激活，随后定量细胞因子 mRNA 水平。
本研究表明，LMP7/MECL1 调节 IFNγ、IL4、IL10、IL2Rβ、GATA3 和 t-bet 的表达。相比之下，蛋白酶体对 IL2、IL13、TNFα 和 IL2Rα 的调节似乎不依赖于 LMP7/MECL1。
综上所述，本研究表明 LMP7 和 MECL1 调节细胞因子表达，表明该系统代表了细胞因子和细胞因子信号转导调节的一种新机制。
