Circulating interleukin‐6 mediates the febrile response to localised inflammation in rats

Abstract

1 Interleukin (IL)‐6 is an important mediator of the host response to disease and has been proposed, largely based upon circumstantial evidence, as the principal endogenous circulating pyrogen responsible for activating CNS mechanisms in fever during infection and inflammation. In the present investigation, we studied the role of peripheral IL‐6 in fever and its relationship with IL‐1, itself an important endogenous pyrogen and a potent stimulus of IL‐6 production. 2 Injection of lipopolysaccharide (LPS) into a sterile, subcutaneous air pouch (i.po.) in rats evoked an increase in body temperature which peaked at 3 h, and which was abolished in animals pretreated (intraperitoneally) with IL‐6 antiserum. 3 The increase in body temperature was accompanied by a significant elevation in concentrations of (immunoreactive) IL‐1 and IL‐6 at the site of inflammation (pouch), but only IL‐6 in the circulation and cerebrospinal fluids. We propose that much of the circulating IL‐6 originates at the site of inflammation, since injection of human recombinant (hr)IL‐6 (i.po.) was detected (10 min after the injection) in the plasma using an ELISA specific for human IL‐6. 4 However, despite the relatively high concentration of IL‐6 injected (25 μg kg−1, i.po.), this cytokine had no effect on body temperature when injected alone, but did induce fever when co‐injected with a non‐pyrogenic dose (when given alone) of IL‐1β, and exacerbated the fever to a pyrogenic dose of IL‐1β. 5 The results from the present study demonstrate that IL‐6 is a circulating endogenous pyrogen during LPS‐induced fever, which acts in concert with IL‐1β at the local site of inflammation, before entering the circulation. Circulating IL‐6 can then activate CNS mechanisms resulting in the development of the febrile response during disease.

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

“…Previous work has suggested that the LPS recognition molecule Toll like receptor 4 (TLR4) on immune cells plays a critical role at the onset of the initial phase of fever, and that the later phases of fever are dependent in a redundant way on TLR4 on both hematopoietic and non-hematopoietic cells (Steiner et al, 2006). While those finding seem to indicate that signaling molecules, such as cytokines, released from immune cells initiates fever, they are in disagreement with the finding that the initiation of the febrile response elicited by intravenously administrated LPS precedes the appearance of IL-6 and other cytokines in the blood stream (Cartmell et al, 2000;Givalois et al, 1994;Roth et al, 1993). …”

“…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.…”

“…IL-6 is a critical proinflammatory cytokine for the febrile response, because neither IL-6 knock-out (IL-6 KO) mice, nor animals treated with IL-6 antiserum develop fever upon peripheral immune stimulation (Cartmell et al, 2000;Chai et al, 1996;Kozak et al, 1998). …”

“…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.…”

“…For example, it has been suggested that IL-6 needs to reach a threshold level to activate the transcription factor STAT3 and initiate fever (Rummel et al, 2004). Another hypothesis is that IL-6 and IL-1 act in a synergistic way, based on the finding that IL-6 induces fever if administered together with a subfebrile dose of IL-1 (Cartmell et al, 2000;Harden et al, 2008). Thus, although the presence of IL-6 has been shown to be necessary for fever, its role in the regulation of the febrile response is not clear.…”