The Role of Interleukin-6 in Lipopolysaccharide-Induced Fever by Mechanisms Independent of Prostaglandin E2

Abstract

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-1beta and TNFalpha or their receptors, and pretreatment of IL-6 knockout mice with soluble TNFalpha 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.

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

“…3). In the WT→WT group intraperitoneal injection of LPS resulted in a typical triphasic fever with the first phase being obscured by the hyperthermia induced by the handling stress associated with the injection, similar to what has previously been reported in WT mice (Nilsberth et al, 2009a;Nilsberth et al, 2009b;Rudaya et al, 2005). KO→KO mice displayed no fever, similar to what is seen in mice with global deletion of the IL-6 gene (Chai et al, 1996).…”

“…A large amount of evidence identifies IL-6 as a necessary factor for the fever response even though IL-6 by itself is not or only weakly or moderately pyrogenic (Cao et al, 2001;Cartmell et al, 2000;Chai et al, 1996;Harden et al, 2008;Kozak et al, 1998;LeMay et al, 1990;Lenczowski et al, 1999;Nilsberth et al, 2009a;Rummel et al, 2006). However, the origin of IL-6 in immune-induced fever has not been fully identified, although there are reports showing that IL-6 can be produced by a variety of cells in response to different pathological stimuli.…”

“…Instead, the endothelial cells in the brain were identified as the main source of PGE 2 important for the fever generation (Engstrom et al, 2012). While IL-6 by itself does not elicit PGE 2 synthesis, it is possible that the febrile response never-the-less could be dependent on IL-6 signaling via brain endothelial cells, through a yet unidentified mechanism (Nilsberth et al, 2009a). IL-6 acts by binding to either a soluble form of its receptor (sIL-6R) (Novick et al, 1989) or to a membrane bound form (IL-6R) (Yamasaki et al, 1988).…”

“…However, depending on species, IL-6 per se has been reported to induce no or only weak to moderate fever (Blatteis, 1990;Cartmell et al, 2000;Dinarello et al, 1991;Harre et al, 2002;Nilsberth et al, 2009a;Rummel et al, 2006;Sakata et al, 1991;Wang et al, 1997). Several explanations for these contradictory observations have been proposed.…”

Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge

“…Etanercept (Enbrel, Wyeth-Ayerst Laboratories, 25 mg/kg) was diluted 1 : 10 in artificial cerebrospinal fluid (aCSF, composition detailed in Supplementary Table S1) and administered intracerebroventricularly (ICV). A total volume of 2 ml was injected as previously established by Nilsberth et al (2009). Eighteen hours post-LPS/saline administration, mice were anesthetized with isoflurane (1%), mounted in a stereotaxic frame, and kept at 37 1C through a feedback-controlled heating pad.…”