Journal
IMMUNOLOGY AND CELL BIOLOGY
Volume 97, Issue 1, Pages 72-84Publisher
WILEY
DOI: 10.1111/imcb.12203
Keywords
Activation protein-1; nuclear receptor corepressor; proinflammatory genes
Categories
Funding
- Ministry of Science and Technology [2016YFA0101300]
- Science and Technology Commission of Shanghai Municipality [16PJ1410200, 15JC1403201]
- NSFC [81530042, 31210103905, 31371510, 31571529, 31571519, 31571390]
- Tongji University (Fundamental Research Funds for the Central Universities) [1500219106, 20002310002]
- Shanghai East Hospital (Chaoyang talent plan) [DFZY-10]
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The role of specific histone deacetylase (HDAC) proteins in regulating the lipopolysaccharide (LPS)-induced inflammatory response and its underlying mechanisms are unclear. Here, HDAC2, a class I HDAC family protein, is essential for the LPS-triggered inflammatory response in macrophages. LPS stimulation increases HDAC2 expression in macrophages. Knockdown of HDAC2 decreases the expression of proinflammatory genes, such as IL-12, TNF-alpha and iNOS following stimulation with LPS. The adoptive transfer of HDAC2 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 HDAC2-mediated LPS-induced production of proinflammatory cytokines. Moreover, HDAC2 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, HDAC2 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 HDAC2/c-Jun signaling network that regulates the LPS-induced immune response in macrophages.
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