title: Methyl CpG binding protein 2 deficiency enhances expression of inflammatory cytokines by sustaining NF-κB signaling in myeloid derived cells.
abstract: Knocking down methyl CpG binding protein 2 (MeCP2) enhances NF-κB activation in human peripheral blood mononuclear cells (PBMC). In this study, we examined whether this caused the expression of cytokines to be elevated. Increased levels of TNFα, IL-6, and IL-3 mRNAs were observed in human PBMC made MeCP2 deficient with a lentiviral shRNA MeCP2 vector and in splenocytes from MeCP2-null mice. TNFα neutralizing antibody attenuated expression of IL-6 and TNFα but did not affect expression of IL-3. Lipopolysaccharide-mediated increases in TNFα, IL-6, and IL-3 mRNAs were also enhanced in MeCP2-deficient PBMC. Two inhibitors of NF-κB blocked the increased levels of IL-6, TNFα, and IL-3 in MeCP2-deficient PBMC treated with lipopolysaccharide. MeCP2 deficiency also enhanced expression of IL-6 and TNFα mRNAs in the THP1 human monocyte cell line, which were also attenuated by the NF-κB inhibitors. In chromatin immunoprecipitation assays, the binding of the NF-κB family member p65 and acetylated H3 to the TNFα promoter was greater after treatment with LPS in MeCP2-deficient THP1 cells. MeCP2 did not bind to the TNFα promoter. In summary, the data indicates that MeCP2 deficiency increases expression of TNFα and other inflammatory cytokines by enhancing NF-κB signaling.
authors.affiliation: Hugo Moser Institute at the Kennedy Krieger, United States; Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States.
authors.forename: Cliona M
authors.initials: CM
authors.lastname: O'Driscoll
authors.affiliation: Hugo Moser Institute at the Kennedy Krieger, United States.
authors.forename: Marina Palma
authors.initials: MP
authors.lastname: Lima
authors.affiliation: Department of Neurology, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Kaufmann
authors.affiliation: Hugo Moser Institute at the Kennedy Krieger, United States; Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States. Electronic address: bressler@kennedykrieger.org.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Bressler
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007249:Inflammation; D007377:Interleukin-3 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000166:cytology; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: C508596:IL3 protein, human; C508600:IL6 protein, human; D007377:Interleukin-3; D015850:Interleukin-6; D008070:Lipopolysaccharides; C497392:MECP2 protein, human; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D016328:NF-kappa B; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha
keywords: Acetylated histone; MeCP2; NF-κB; Peripheral blood mononuclear cells; TNFα; p65