1. Activation of IL-1β and TNFα genes is mediated by the establishment of permissive chromatin structures during monopoiesis.
- Author
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Wessels I, Rosenkranz E, Ventura Ferreira M, Neuss S, Zenke M, Rink L, and Uciechowski P
- Subjects
- Acetylation drug effects, Cell Differentiation drug effects, Cell Differentiation genetics, Cells, Cultured, Chromatin drug effects, Chromatin metabolism, Enzyme-Linked Immunosorbent Assay, Granulocytes cytology, Granulocytes metabolism, HL-60 Cells, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Histone Deacetylase Inhibitors pharmacology, Humans, Hydroxamic Acids pharmacology, Interleukin-1beta metabolism, Monocytes cytology, Myelopoiesis genetics, Neutrophils cytology, Neutrophils metabolism, Promoter Regions, Genetic genetics, Reverse Transcriptase Polymerase Chain Reaction, Transcriptional Activation drug effects, Tumor Necrosis Factor-alpha metabolism, Chromatin genetics, Interleukin-1beta genetics, Monocytes metabolism, Tumor Necrosis Factor-alpha genetics
- Abstract
IL-1β and TNFα participate in a wide range of immunoregulatory activities. The overproduction of these cytokines can result in inflammatory and autoimmune diseases. Monocytes are the main producers of both cytokines. In contrast, studies with highly purified polymorphonuclear leukocytes (PMN) showed their inability to synthesize IL-1β and TNFα. Mature monocytes and PMN are derived from the same precursors. However, the reason for the differential IL-1β and TNFα expression is not elucidated. Our study investigates the epigenetic mechanisms that may explain this apparent discrepancy. The expression and promoter accessibilities of IL-1β and TNFα genes of primary and in vitro differentiated monocytes and PMN and their common precursors were compared. The effects of histone deacetylase (HDAC)-inhibition by trichostatin A (TSA) on IL-1β and TNFα expression and their promoter structures were measured in promyeloid HL-60 cells. Cytokine expression was assessed by real-time PCR and ELISA. Chromatin structures were analyzed using chromatin accessibility by real-time PCR (CHART) assay. The proximal IL-1β promoter was remodeled into an open conformation during monopoiesis, but not granulopoiesis. Although stimulation-dependent, remodeling of the TNFα promoter was again only observed in monocytes. TSA activated IL-1β and TNFα expression and supported chromatin remodeling of their promoters in HL-60 cells. The ability to express IL-1β and TNFα is linked to a cell type specific promoter structure, which is established during monocytic but not granulocytic differentiation. The participation of acetylation in IL-1β and TNFα promoter activation shed new light on the regulation of IL-1β or TNFα expression. These data may have implications for understanding the progression from normal to disease conditions., (Copyright © 2012 Elsevier GmbH. All rights reserved.)
- Published
- 2013
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