Intracellular mammalian DNA stimulates myeloid dendritic cells to produce type I interferons predominantly through a toll-like receptor 9-independent pathway

Arthritis and Rheumatism
David A Martin, Keith B Elkon

Abstract

Exogenous nucleic acids, including bacterial unmethylated DNA and viral single-stranded RNA, are potent activators of innate immunity through interaction with the Toll-like receptors (TLRs). In contrast, mammalian DNA has been generally thought to have a limited activation effect, or even a suppressive effect, on innate immunity. Since DNA is a major component of dying cells and recent studies indicate that mammalian nucleic acids may be stimulatory under certain conditions, we undertook this study to examine the effect of intracellular mammalian DNA on myeloid dendritic cell (DC) activation. Mammalian DNA was introduced into murine bone marrow-derived DCs (BMDCs) by transfection. BMDC activation was determined by flow cytometry (CD40, CD86). Production of tumor necrosis factor alpha and interleukin-6 was measured by enzyme-linked immunosorbent assay, and production of type I interferons (IFNs) by bioassay. Parallel studies were conducted using BMDCs from mice deficient in myeloid differentiation 88 (MyD88), TLR-9, and IFNalpha/beta receptor. Intracellular mammalian DNA activated immature BMDCs, as determined by the up-regulation of CD40 and CD86 as well as by the production of significant quantities of type I IFN. The interfer...Continue Reading

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