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Tet methylcytosine dioxygenase 2 (Tet2) mediates demethylation of DNA. We here sought to determine the expression and function of Tet2 in macrophages upon exposure to lipopolysaccharide (LPS), and in the host response to LPS induced lung and peritoneal inflammation, and during <i>Escherichia (E.) coli</i> induced peritonitis. LPS induced <i>Tet2</i> expression in mouse macrophages and human monocytes in vitro, as well as in human alveolar macrophages after bronchial instillation in vivo. Bone marrow-derived macrophages from myeloid Tet2 deficient (<i>Tet2^fl/flLysM^Cre</i>) mice displayed enhanced production of IL-1β, IL-6 and CXCL1 upon stimulation with several Toll-like receptor agonists; similar results were obtained with LPS stimulated alveolar and peritoneal macrophages. Histone deacetylation was involved in the effect of Tet2 on IL-6 production, whilst methylation at the <i>Il6</i> promoter was not altered by Tet2 deficiency. <i>Tet2^fl/flLysM^Cre</i> mice showed higher IL-6 and TNF levels in bronchoalveolar and peritoneal lavage fluid after intranasal and intraperitoneal LPS administration, respectively, whilst other inflammatory responses were unaltered. <i>E. coli</i> induced stronger production of IL-1β and IL-6 by Tet2 deficient peritoneal macrophages but not in peritoneal lavage fluid of <i>Tet2^fl/flLysM^Cre</i> mice after in vivo intraperitoneal infection. <i>Tet2^fl/flLysM^Cre</i> mice displayed enhanced bacterial growth during <i>E. coli</i> peritonitis, which was associated with a reduced capacity of <i>Tet2^fl/flLysM^Cre</i> peritoneal macrophages to inhibit the growth of <i>E. coli</i> in vitro. Collectively, these data suggest that Tet2 is involved in the regulation of macrophage functions triggered by LPS and during <i>E. coli</i> infection.