Inflammation promotes the removal of factors that cause tissue injury; however, if not properly resolved, prolonged inflammation can itself be damaging to tissues and the organism. Dynamic epigenetic modifications, such as acetylation and methylation, of histones and DNA regulate gene expression. In cultured murine bone marrow–derived dendritic cells (mBMDCs), murine peritoneal macrophages, and human dendritic cells, Zhang et al. found that loss of Tet2, an enzyme that catalyzes DNA demethylation, caused the expression of genes encoding proinflammatory molecules, including interleukin-6 (IL-6), to remain high during the late-phase response to lipopolysaccharide (LPS), when gene expression would normally subside. In mouse models of colitis and endotoxin shock, mice with a myeloid cell–specific lack of Tet2 produced more late-phase IL-6 and had greater colon or lung tissue damage and inflammation, respectively, than did control mice. Tet2-deficient mBMDCs and macrophages had prolonged IL-6 production compared with control cells despite exhibiting a similar activation and termination profile of upstream signaling pathways. Coimmunoprecipitation coupled with mass spectrometry analysis revealed that by interacting with the transcription factor IκBζ, Tet2 bound to the Il6 promoter during the late-phase LPS response of cultured mBMDCs. Curiously, IκBζ enhances Il6 transcription in early phases of the LPS response by recruiting a transcription complex involving RelA; thus, it appears that its selectivity for binding partners may somehow be triggered to change in later phases to repress Il6 transcription. Cytokine production during the innate immune response is regulated by the epigenetic modification of histone tails, specifically lysine acetylation. In mBMDCs and macrophages, the abundance of acetylation on histones 3 and 4 at the Il6 promoter was positively correlated with the amount of Il6 mRNA. In cells and in vitro, Tet2 interacted with the histone deacetylases HDAC1 and HDAC2. Unlike that of HDAC1, however, the amount of HDAC2 binding to the Il6 promoter in mBMDCs and macrophages was suppressed in early phases, but increased in later phases of the LPS response, an effect that was not observed in the absence of Tet2. Similar to Tet2 deficiency, inhibiting or knocking down HDAC2 increased the prolonged expression of Il6 in response to LPS, and sequential chromatin immunoprecipitation and yeast two-hybrid assays revealed that Tet2 recruited HDAC2 to the Il6 promoter. Together, these findings elucidate the epigenetic mechanisms underlying the resolution of inflammation.
Q. Zhang, K. Zhao, Q. Shen, Y. Han, Y. Gu, X. Li, D. Zhao, Y. Liu, C. Wang, X. Zhang, X. Su, J. Liu, W. Ge, R. L. Levine, N. Li, X. Cao, Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389–393 (2015). [PubMed]