Regulation of arginase-1 expression in macrophages by a protein kinase A type I and histone deacetylase dependent pathway.
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.
Haffner
Ivonne
I
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Liebigstrasse 27, 04103 Leipzig, Germany.
Teupser
Daniel
D
Holdt
Lesca M
LM
Ernst
Jana
J
Burkhardt
Ralph
R
Thiery
Joachim
J
D000107:Acetylation; D000818:Animals; D001119:Arginase / Q000096:biosynthesis* / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology*; D054743:Cyclic AMP-Dependent Protein Kinase Type I / Q000502:physiology*; D054746:Cyclic AMP-Dependent Protein Kinase Type II / Q000502:physiology; D004789:Enzyme Activation; D004790:Enzyme Induction / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D011499:Protein Processing, Post-Translational; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D015290:Second Messenger Systems / Q000502:physiology
D001549:Benzamides; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011725:Pyridines; D012333:RNA, Messenger; C118739:entinostat; C012589:trichostatin A; D000242:Cyclic AMP; D054743:Cyclic AMP-Dependent Protein Kinase Type I; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D006655:Histone Deacetylases; D001119:Arginase