Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response.
Patients who survive sepsis have significant deficiencies in their immune responses caused by poorly understood mechanisms. We have explored this phenomenon by studying dendritic cells (DCs) recovered from animals surviving severe peritonitis-induced sepsis, using the well-established cecal ligation and puncture (CLP) model. Immediately after the initiation of sepsis there is a depletion in DCs from the lung and spleen, which is followed by repopulation of these cells back to the respective organs. DCs recovered from surviving animals exhibited a significant and chronic suppression of interleukin-12 (IL-12), a key host defense cytokine. The suppression of DC-derived IL-12 persisted for at least 6 weeks after CLP and was not due to immunoregulatory cytokines, such as IL-10. Using chromatin immunoprecipitation (ChIP) techniques, we have shown that the deficiency in DC-derived IL-12 was due to epigenetic alterations. Specifically, IL-12 expression was regulated by stable reciprocal changes in histone H3 lysine-4 trimethylation (H3K4me3) and histone H3 lysine-27 dimethylation (H3K27me2), as well as changes in cognate histone methyltransferase (HMT) complexes on the Il12p35 and Il12p40 promoters. These data implicate histone modification enzymes in suppressing DC-derived IL-12, which may provide one of the mechanisms of long-term immunosuppression subsequent to the septic response.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Haitao
H
Wen
Yali
Y
Dou
Cory M
CM
Hogaboam
Steven L
SL
Kunkel
D000818:Animals; D002432:Cecum; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D007113:Immunity, Innate; D007165:Immunosuppression Therapy; D018664:Interleukin-12 / Q000235:genetics*; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013154:Spleen / Q000276:immunology
D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D018664:Interleukin-12; D010047:Ovalbumin