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

Interleukin-6 (IL-6) is critical for the lipopolysaccharide (LPS)-induced febrile response. However, the exact source(s) of IL-6 involved in regulating the LPS-elicited fever is still to be identified. One known source of IL-6 is hematopoietic cells, such as monocytes. To clarify the contribution of hematopoietically derived IL-6 to fever, we created chimeric mice expressing IL-6 selectively either in cells of hematopoietic or, conversely, in cells of non-hematopoietic origin. This was performed by extinguishing hematopoietic cells in wild-type (WT) or IL-6 knockout (IL-6 KO) mice by whole-body irradiation and transplanting them with new stem cells. Mice on a WT background but lacking IL-6 in hematopoietic cells displayed normal fever to LPS and were found to have similar levels of IL-6 protein in the cerebrospinal fluid (CSF) and in plasma and of IL-6 mRNA in the brain as WT mice. In contrast, mice on an IL-6 KO background, but with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on a WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of non-hematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.

The role of interleukin-6 in lipopolysaccharide-induced fever by mechanisms independent of prostaglandin E2.

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.