期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 95, 期 4, 页码 651-659出版社
WILEY
DOI: 10.1189/jlb.1013565
关键词
inflammation; inhibitors; cytokine; macrophages
资金
- National Nature Science Foundation of China [81070940, 81271301, 81171965]
- High Level Innovative Talent Recruitment Plan of Jiangsu Province, PR China
- National Basic Research Program of China 973 Program [2012CB517605]
HDAC1, 2, and 3 isoforms regulate innate immune responses by deacetylating MKP-1, and are potential therapeutic targets in inflammatory diseases. 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-, IL-1, 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.
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