Type I diabetes (T1DM) is characterized by hyperglycemia and insulin deficiency. T1DM is associated with constitutive production of pro-inflammatory cytokine such as the members of IL-1 family. IL-1β binding to its MyD88-associated receptor IL-1R is a major cause of tissue injury in T1DM. We hypothesize that hyperglycemia (HG) enhances MyD88 in macrophages (MA) amplifying IL-1βR responsiveness. We found that both in vitro and in vivo HG increases the expression of MyD88 and its transcription factor STAT-1. Speculating that enhanced MyD88/STAT-1 levels could be due to epigenetic changes, we analyzed the expression of enzymes involved in DNA methylation (DNMT) and Histone deacetylation (HDAC) in MA from T1DM mice. We observed that diabetic mice expressed at least 2 times more HDAC 8, 10 and 11, and DNMT 3b than nondiabetic mice. In vitro inhibition of HDAC (TSA) or DNMT (5-azacyd) in MA impaired HG-enhanced MyD88 and STAT-1 expression. These data suggest a heretofore unrecognized epigenetic changes associated with hyperinflammatory pattern of MA from T1DM, leading to high MyD88 expression and possibly allowing overly IL-1β receptor and other MyD88-dependent receptor activation
- Copyright © 2013 by The American Association of Immunologists, Inc.