Facultative heterochromatin formation at the IL-1 beta promoter in LPS tolerance and sepsis

The clinical phenotype in sepsis that is observed as LPS tolerance is determined by silencing of proinflammatory genes like IL-1 beta (IL-1 beta). This study shows that facultative heterochromatin (fHC) silences IL-1 beta expression during sepsis, where we find dephosphorylated histone H3 serine 10 and increased binding of heterochromatin protein-1 (HP-1) to the promoter. In both human sepsis blood leukocytes and an LPS tolerant human THP-1 cell model, we show that I kappa beta alpha and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) function as dominant labile mediators of fHC formation at the IL-1 beta promoter. Protein synthesis inhibition decreases levels of Mkt and RelB, converts silent fHC to euchromatin, and restores IL-1 beta transcription. We further show TLR dependent NF kappa B p65 and histone H3 serine 10 phosphorylation binding at the promoter. We conclude that the resolution phase of sepsis, which correlates with survival in humans, may depend on the plasticity of chromatin structure as found in fHC. (C) 2010 Elsevier Ltd. All rights reserved.