Haffner Ivonne, Teupser Daniel, Holdt Lesca M, Ernst Jana, Burkhardt Ralph, Thiery Joachim
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Liebigstrasse 27, 04103 Leipzig, Germany.
J Cell Biochem. 2008 Feb 1;103(2):520-7. doi: 10.1002/jcb.21422.
The aim of the current study was to investigate the cAMP-dependent regulation of arginase-1 (ARG1) expression in RAW-macrophages. Basal ARG1 mRNA expression was low and increased upon incubation with the cAMP analogue Br-cAMP. We used selective agonists of protein kinase A type I (PKAI), type II (PKAII) and exchange protein directly activated by cAMP (EPAC) to determine the pathway responsible for ARG1 expression. Activation of PKAI led to a significant up-regulation of ARG1 mRNA expression and arginase enzyme activity. In contrast, neither activation of PKAII nor activation of EPAC affected ARG1 expression. In addition, it has been shown that histone deacetylase (HDAC) activity plays a critical role in cAMP-dependent transcriptional regulation. Incubation with Br-cAMP and the HDAC inhibitor trichostatin A (TSA) led to a concentration-dependent suppression of ARG1 expression. These data indicate that cAMP-dependent activation of ARG1 expression is mediated by PKAI and requires histone deacetylation.
本研究的目的是探讨RAW巨噬细胞中cAMP依赖性精氨酸酶-1（ARG1）表达的调控机制。基础ARG1 mRNA表达水平较低，与cAMP类似物Br-cAMP孵育后表达增加。我们使用蛋白激酶A I型（PKAI）、II型（PKAII）和直接由cAMP激活的交换蛋白（EPAC）的选择性激动剂来确定负责ARG1表达的信号通路。PKAI的激活导致ARG1 mRNA表达和精氨酸酶活性显著上调。相反，PKAII的激活和EPAC的激活均不影响ARG1的表达。此外，已有研究表明组蛋白去乙酰化酶（HDAC）活性在cAMP依赖性转录调控中起关键作用。与Br-cAMP和HDAC抑制剂曲古抑菌素A（TSA）孵育导致ARG1表达呈浓度依赖性抑制。这些数据表明，ARG1表达的cAMP依赖性激活是由PKAI介导的，并且需要组蛋白去乙酰化。
