title: Histone deacetylase isoforms regulate innate immune responses by deacetylating mitogen-activated protein kinase phosphatase-1.
abstract: The MAPK pathway mediates TLR signaling during innate immune responses. We discovered previously that MKP-1 is acetylated, enhancing its interaction with its MAPK substrates and deactivating TLR signaling. As HDACs modulate inflammation by deacetylating histone and nonhistone proteins, we hypothesized that HDACs may regulate LPS-induced inflammation by deacetylating MKP-1. We found that mouse macrophages expressed a subset of HDAC isoforms (HDAC1, HDAC2, and HDAC3), which all interacted with MKP-1. Genetic silencing or pharmacologic inhibition of HDAC1, -2, and -3 increased MKP-1 acetylation in cells. Furthermore, knockdown or pharmacologic inhibition of HDAC1, -2, and -3 decreased LPS-induced phosphorylation of the MAPK member p38. Also, pharmacologic inhibition of HDAC did not decrease MAPK signaling in MKP-1 null cells. Finally, inhibition of HDAC1, -2, and -3 decreased LPS-induced expression of TNF-α, IL-1β, iNOS (NOS2), and nitrite synthesis. Taken together, our results show that HDAC1, -2, and -3 deacetylate MKP-1 and that this post-translational modification increases MAPK signaling and innate immune signaling. Thus, HDAC1, -2, and -3 isoforms are potential therapeutic targets in inflammatory diseases.
authors.affiliation: 2.Jiangsu Key Lab of Molecular Medicine, 22 Hankou Rd., Nanjing, China, 210093. wangsencao@nju.edu.cn.
authors.forename: Youngtae
authors.initials: Y
authors.lastname: Jeong
authors.forename: Ronghui
authors.initials: R
authors.lastname: Du
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhu
authors.forename: Shasha
authors.initials: S
authors.lastname: Yin
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Hengmi
authors.initials: H
authors.lastname: Cui
authors.forename: Wangsen
authors.initials: W
authors.lastname: Cao
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lowenstein
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D006655:Histone Deacetylases / Q000502:physiology*; D007113:Immunity, Innate; D007249:Inflammation / Q000209:etiology; D007527:Isoenzymes / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D006655:Histone Deacetylases
keywords: cytokine; inflammation; inhibitors; macrophages