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Histone deacetylase 2 is essential for LPS ‐induced inflammatory responses in macrophages
Author(s) -
Wu Chenming,
Li Ang,
Hu Jian,
Kang Jiuhong
Publication year - 2019
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1111/imcb.12203
Subject(s) - proinflammatory cytokine , histone deacetylase 2 , gene knockdown , histone deacetylase , corepressor , microbiology and biotechnology , chromatin immunoprecipitation , lipopolysaccharide , transactivation , chemistry , transcription factor , biology , histone , cancer research , inflammation , gene expression , immunology , promoter , nuclear receptor , biochemistry , apoptosis , gene
The role of specific histone deacetylase ( HDAC ) proteins in regulating the lipopolysaccharide ( LPS )‐induced inflammatory response and its underlying mechanisms are unclear. Here, HDAC 2, a class I HDAC family protein, is essential for the LPS ‐triggered inflammatory response in macrophages. LPS stimulation increases HDAC 2 expression in macrophages. Knockdown of HDAC 2 decreases the expression of proinflammatory genes, such as IL ‐12, TNF ‐α and iNOS following stimulation with LPS . The adoptive transfer of HDAC 2 knockdown macrophages attenuates the LPS ‐triggered innate inflammatory response in vivo , and these mice are less sensitive to endotoxin shock and Escherichia coli ‐induced sepsis. Mechanistically, the c‐Jun protein is the main target of HDAC 2‐mediated LPS ‐induced production of proinflammatory cytokines. Moreover, HDAC 2 knockdown increases the expression of c‐Jun, which directly binds the promoters of proinflammatory genes and forms nuclear receptor corepressor complexes to inhibit the transcription of proinflammatory genes in macrophages. These effects are rescued by c‐Jun expression. According to the chromatin immunoprecipitation analysis, HDAC 2 also selectively suppresses c‐Jun expression by directly binding to its promoter and modifying histone acetylation after LPS stimulation. Our findings define a new function and mechanism of the HDAC 2/c‐Jun signaling network that regulates the LPS ‐induced immune response in macrophages.