Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response

Haitao Wen, Yali Dou, Cory M. Hogaboam, Steven L. Kunkel

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1797-1804
Number of pages8
JournalBlood
Volume111
Issue number4
DOIs
StatePublished - Feb 15 2008

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Interleukin-12
Innate Immunity
Epigenomics
Immunosuppression
Dendritic Cells
Histones
Sepsis
Punctures
Lysine
Ligation
Animals
Histone Code
Cytokines
Chromatin Immunoprecipitation
Peritonitis
Interleukin-10
Chromatin
Spleen
Lung
Enzymes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response. / Wen, Haitao; Dou, Yali; Hogaboam, Cory M.; Kunkel, Steven L.

In: Blood, Vol. 111, No. 4, 15.02.2008, p. 1797-1804.

Research output: Contribution to journalArticle

Wen, Haitao ; Dou, Yali ; Hogaboam, Cory M. ; Kunkel, Steven L. / Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response. In: Blood. 2008 ; Vol. 111, No. 4. pp. 1797-1804.
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