Abstracts (complete list) - Wissenschaft Online

Mirjam Peter, Klaus Heeg, Alexander Dalpke
Characterization of a guanosine-rich suppressive
oligodesoxynucleotide which inhibits Toll-like receptor-9
signaling
Bacterial DNA as well as synthetic oligonucleotides containing unmethylated CpG
sequences (CpG-ODN) activate immune cells by stimulating Toll-like receptor 9 (TLR9).
This activation leads to cytokine secretion and up-regulation of costimulatory molecules
in macrophages and dendritic cells (DCs) as well as B-lymphocyte proliferation. Beside
these physiological effects TLR9 activation is accused to be responsible for the onset
and aggravation of autoimmune diseases. Recently, suppressive ODN have been
described which inhibit TLR9 induced activation of immune cells. Here we describe a
novel guanosine-rich, suppressive ODN (G-ODN) which inhibits CpG induced activation
of TLR9 in murine macrophages and DCs as well as in human plasmacytoid DCs (pDCs).
G-ODN blocked the secretion of TNFα and IL12p40 as well as up-regulation of
costimulatory molecules. We observed an early block of signaling as activation of MAP-
Kinases and NF-κB was inhibited but G-ODN did not inerfere with cellular uptake.
Inhibition was TLR9 specific as it was not observed for stimulation of other TLRs. This
was confirmed using a TLR9 specific transfection model. G-ODNs even inhibited in a
molar ratio of 10:1 and were also inhibitory when given up to 6 hours after initial CpG
stimulation. G-ODNs were also suppressive in an in vivo model of CpG-induced cytokine
shock. Therefore this class of G-ODN could be of therapeutic use in clinical situations
with increased TLR9 activation as suggested for certain autoimmune diseases.