A critical role of CpG motifs in a murine peritonitis model by their binding to highly expressed toll-like receptor-9 on liver NKT cells.
BACKGROUND
Toll-like receptor (TLR)-9 plays a critical role in the recognition of the CpG motifs, which is frequently observed in bacterial DNA. To date, there have not been any reports regarding the role of bacterial DNA in the systemic circulation on the development of sepsis.


METHODS
We examined the expression of TLR-9 in the liver and spleen in a murine peritonitis model (CLP mice). We also measured the cytokine response of mononuclear cells (MNCs) from normal and CLP mice to CpG oligodeoxynucleotides (ODN) in vitro and in vivo.


RESULTS
TLR-9 expression on F4/80(+) and NK1.1(+)CD3epsilon(+) cells in the liver of CLP mice was elevated compared to sham-operated mice. With regard to cytokine production, we found that CpG ODN markedly stimulated the production of inflammatory cytokines by murine macrophages and liver MNCs. The intravenous injection of CpG ODN in mice that underwent CLP 12h earlier led to their increased cytokine production and their increased mortality. In addition, the depletion of NK/NKT cells contributed to improve their survival rate.


CONCLUSIONS
Our results suggest that, in patients with overwhelming bacterial infection, bacterial DNA may induce liver toxicity that is mediated by liver NKT cells and macrophages that express high levels of TLR-9.
Tsujimoto
Hironori
H
Department of Surgery I, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. Tsujiflorida@aol.com
Ono
Satoshi
S
Matsumoto
Atsushi
A
Kawabata
Toshinobu
T
Kinoshita
Manabu
M
Majima
Takashi
T
Hiraki
Shuichi
S
Seki
Shuhji
S
Moldawer
Lyle L
LL
Mochizuki
Hidetaka
H
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000494:pharmacology; D020816:Amino Acid Motifs; D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology*; D010538:Peritonitis / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis / Q000235:genetics*
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9