Pyrogenicity of CpG-DNA in mice: role of interleukin-6, cyclooxygenases, and nuclear factor-kappaB.
نویسندگان
چکیده
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.
منابع مشابه
CALL FOR PAPERS Physiology and Pharmacology of Temperature Regulation Pyrogenicity of CpG-DNA in mice: role of interleukin-6, cyclooxygenases, and nuclear factor- B
Kozak, Wieslaw, Sylwia Wrotek, and Anna Kozak. Pyrogenicity of CpG-DNA in mice: role of interleukin-6, cyclooxygenases, and nuclear factorB. Am J Physiol Regul Integr Comp Physiol 290: R871–R880, 2006. First published November 17, 2005; doi:10.1152/ajpregu.00408.2005.— Bacterial DNA containing unmethylated cytosine-phosphate-guanosine motif (CpG-DNA) has been identified as a pathogen-associated...
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ورودعنوان ژورنال:
- American journal of physiology. Regulatory, integrative and comparative physiology
دوره 290 4 شماره
صفحات -
تاریخ انتشار 2006