Pyrogenicity of CpG-DNA in mice: role of interleukin-6, cyclooxygenases, and nuclear factor-kappaB.
Bacterial DNA containing unmethylated cytosine-phosphate-guanosine motif (CpG-DNA) has been identified as a pathogen-associated molecular pattern, which is recognized by Toll-like receptors and activates immune cells to produce cytokines. The aim of the study was to characterize the ability of CpG-DNA to induce fever in mice. Intravenous administration of unmethylated CpG-DNA 1826 triggered an elevation of body temperature (T(b)) lasting several hours. The magnitude of T(b) elevation increased with an increase of dose of the oligonucleotide (administered in a range from 0.01 mg/kg to 1.0 mg/kg). A fever-like increase of T(b) in mice was partially dependent on IL-6, as IL-6 deficient mice responded with reduced fever to the CpG-DNA 1826. Meloxicam and sulindac sulfide, inhibitors of cyclooxygenases, reduced fever in mice challenged with CpG-DNA 1826, indicating that the process may also depend on prostaglandins. In fact, plasma levels of prostaglandin E(2), as well as IL-6, increased at 4 h postinjection of CpG-DNA 1826 into mice. These data demonstrate that the pathophysiological mechanism of the increase of T(b) induced by CpG-DNA 1826 is similar to fever induced by LPS. Both LPS and CpG-DNA 1826 failed to produce elevation of T(b) in mice deficient for a nuclear factor-kappaB (NF-kappaB) gene, further supporting the hypothesis that the two pyrogens provoke fever, using the same components of the cellular signaling metabolism. However, parthenolide, an inhibitor of I-kappaB kinase reduced fever due to CpG-DNA 1826, and did not affect fever to LPS, suggesting that the two structurally dissimilar pyrogens may affect different intracellular pathways leading to the upregulation of NF-kappaB. In support of this hypothesis, we demonstrate that C3H/HeJ mice, known to exhibit a mutation in the Toll-like receptor-4 gene, do not respond with fever to LPS. They respond, however, with fever after injection of CpG-DNA 1826. We conclude that bacterial DNA shares with components of the bacterial wall the capacity to elicit fever and may, consequently, be part of a novel class of exogenous pyrogens.
Kozak
Wieslaw
W
Department of Immunology, Institute of General and Molecular Biology, Faculty of Biology and Earth Sciences, Nicolaus Copernicus University, 9 Gagarina St., 87-100 Torun, Poland. wkozak@biol.uni.torun.pl
Wrotek
Sylwia
S
Kozak
Anna
A
D000818:Animals; D018899:CpG Islands / Q000502:physiology*; D004247:DNA / Q000502:physiology; D015232:Dinoprostone / Q000097:blood; D005334:Fever / Q000139:chemically induced; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011749:Pyrogens / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction; D013696:Temperature; D051193:Toll-Like Receptors / Q000378:metabolism
D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011749:Pyrogens; D012717:Sesquiterpenes; D051193:Toll-Like Receptors; C002669:parthenolide; D004247:DNA; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone