BACKGROUND/AIMS: Bacterial DNA and synthetic oligonucleotides containing unmethylated motifs have become the focus of many studies due to their ability to activate cells of the innate immune system through interaction with Toll-like receptor 9 (TLR9). This study was undertaken to investigate if and how CpG-oligonucleotides (CpGs) activate liver sinusoidal endothelial cells (LSECs), known to be the main site of clearance of DNA-oligonucleotides from the circulation. METHODS: Expression of TLR9 was analyzed by RT-PCR and immunohistochemistry. Production of IL-1beta and IL-6 was measured by ELISA. RESULTS: Here we show for the first time that mouse LSECs express TLR9 mRNA and protein. Moreover, our findings suggest that CpGs are first taken up by LSECs by scavenger receptor(s)-mediated endocytosis, and then join TLR9 in the lysosomal compartments. Furthermore, we found that uptake of CpGs in LSECs results in the activation of transcription factor NF-kappaB and secretion of IL-1beta and IL-6. CONCLUSIONS: The presence of functional TLR9 in LSECs emphasizes the importance of these cells in the innate defense mechanisms of the liver.
BACKGROUND/AIMS: Bacterial DNA and synthetic oligonucleotides containing unmethylated motifs have become the focus of many studies due to their ability to activate cells of the innate immune system through interaction with Toll-like receptor 9 (TLR9). This study was undertaken to investigate if and how CpG-oligonucleotides (CpGs) activate liver sinusoidal endothelial cells (LSECs), known to be the main site of clearance of DNA-oligonucleotides from the circulation. METHODS: Expression of TLR9 was analyzed by RT-PCR and immunohistochemistry. Production of IL-1beta and IL-6 was measured by ELISA. RESULTS: Here we show for the first time that mouse LSECs express TLR9 mRNA and protein. Moreover, our findings suggest that CpGs are first taken up by LSECs by scavenger receptor(s)-mediated endocytosis, and then join TLR9 in the lysosomal compartments. Furthermore, we found that uptake of CpGs in LSECs results in the activation of transcription factor NF-kappaB and secretion of IL-1beta and IL-6. CONCLUSIONS: The presence of functional TLR9 in LSECs emphasizes the importance of these cells in the innate defense mechanisms of the liver.
Authors: Jaione Simon-Santamaria; Ivana Malovic; Alessandra Warren; Ana Oteiza; David Le Couteur; Bård Smedsrød; Peter McCourt; Karen Kristine Sørensen Journal: J Gerontol A Biol Sci Med Sci Date: 2010-06-24 Impact factor: 6.053