The Role of Interleukin-6 in Lipopolysaccharide-Induced Fever by Mechanisms Independent of Prostaglandin E-2
2009 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 150, no 4, 1850-1860 p.Article in journal (Refereed) Published
Fever has been shown to be elicited by prostaglandin E-2 (PGE(2)) binding to its receptors on thermoregulatory neurons in the anterior hypothalamus. The signals that trigger PGE(2) production are thought to include proinflammatory cytokines, such as IL-6. However, although the presence of IL-6 is critical for fever, IL- 6 by itself is not or only weakly pyrogenic. Here we examined the relationship between IL-6 and PGE(2) in lipopolysaccharide (LPS)-induced fever. Immune-challenged IL- 6 knockout mice did not produce fever, in contrast to wild-type mice, but the expression of the inducible PGE(2)-synthesizing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase-1, was similarly up-regulated in the hypothalamus of both genotypes, which also displayed similarly elevated PGE(2) levels in the cerebrospinal fluid. Nevertheless, both wild-type and knockout mice displayed a febrile response to graded concentrations of PGE(2) injected into the lateral ventricle. There was no major genotype difference in the expression of IL-1 beta and TNF alpha or their receptors, and pretreatment of IL- 6 knockout mice with soluble TNF alpha receptor ip or intracerebroventricularly or a cyclooxygenase-2 inhibitor ip did not abolish the LPS unresponsiveness. Hence, although IL- 6 knockout mice have both an intact PGE(2) synthesis and an intact fever-generating pathway downstream of PGE(2), endogenously produced PGE(2) is not sufficient to produce fever in the absence of IL-6. The findings suggest that IL- 6 controls some factor(s) in the inflammatory cascade, which render(s) IL- 6 knockout mice refractory to the pyrogenic action of PGE(2), or that it is involved in the mechanisms that govern release of synthesized PGE(2) onto its target neurons.
Place, publisher, year, edition, pages
2009. Vol. 150, no 4, 1850-1860 p.
National CategoryMedical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-17620DOI: 10.1210/en.2008-0806OAI: oai:DiVA.org:liu-17620DiVA: diva2:210917