title: Facultative heterochromatin formation at the IL-1 beta promoter in LPS tolerance and sepsis.
abstract: The clinical phenotype in sepsis that is observed as LPS tolerance is determined by silencing of pro-inflammatory genes like IL-1 beta (IL-1β). This study shows that facultative heterochromatin (fHC) silences IL-1β 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 IκBα and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) function as dominant labile mediators of fHC formation at the IL-1β promoter. Protein synthesis inhibition decreases levels of IκBα and RelB, converts silent fHC to euchromatin, and restores IL-1β transcription. We further show TLR dependent NFκB 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.
authors.affiliation: Department of Surgery, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA. byoza@wfubmc.edu
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Yoza
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCall
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects* / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D018805:Sepsis / Q000235:genetics*; D051996:Transcription Factor RelA / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D006570:Heterochromatin; D006657:Histones; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D051841:Transcription Factor RelB