Delineation of the Proinflammatory Cytokine Cascade in Fever Induction^a

Abstract

Bacterial lipopolypolysaccharide (LPS)-induced fever involves induction of the proinflammatory cytokines interleukin (IL)-1 alpha, IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), and IL-6, both in the periphery and in the brain. These molecules can induce expression of each other and also regulate expression of their own receptors in a complex manner. The functional hierarchy of these highly inducible proteins is therefore difficult to determine. Using mice strains carrying the null mutations of IL-1 beta, IL-1RI, IL-1RAcP, or IL-6, respectively, we show that LPS-induced fever involves IL-1 beta, which acts at a complex consisting of the type I IL-1 receptor and the IL-1RAcP. This action occurs prior to central IL-6 release, which has been shown to be a necessary component of fever responses induced by LPS, IL-1 beta, and also TNF-alpha. In the absence of IL-1 beta, as in IL-1 beta-deficient mice, LPS, IL-1 alpha, and IL-1 beta cause hyperresponsive fevers when exogenously applied. Murine TNF-alpha is a poor pyrogen in mice even when mice are kept at thermoneutral temperature (30 degrees C). TNF-alpha-mediated fever depends on central IL-6 expression.

Effects of i.c.v. administration of interleukin-1 on sleep and body temperature of interleukin-6-deficient mice

“…Of importance to this present study, low doses of LPS administered intraperitoneally (IP) do not induce fever in IL-6 KO mice (Kozak et al, 1998;Zetterstrom et al, 1998;Morrow and Opp, 2005a). Similarly, IL-6 KO mice do not fever in response to IP administration of IL-1 (Chai et al, 1996).…”

“…Similarly, IL-6 KO mice do not fever in response to intravenous administration of IL-1α (Kagiwada et al, 2004). In addition, IP administration of low doses of LPS does not induce fever in IL-6 KO mice (Chai et al, 1996;Kozak et al, 1998;Zetterstrom et al, 1998;Morrow and Opp, 2005a). However, IL-6 KO mice develop fever after ICV administration of recombinant human IL-6 (Chai et al, 1996).…”

Behavioral fever in ectothermic vertebrates

“…Notably, their activation induces the release of pyrogenic cytokines called endogenous pyrogens such as interleukin (IL) 1b, IL6, tumor necrosis factor a (TNFa), and interferons (IFN) (Dinarello, 1999;Netea et al, 2000). Both IL1b and TNFa can induce the expression of each other (Dinarello et al, 1986;Ikejima et al, 1990) and are potent inducers of IL6 (Zetterstrom et al, 1998), which on contrary tends to be an inhibitor of IL1b and TNFa production (Netea et al, 2000;Schindler et al, 1990). IL6 seems to be the major mediator for sustaining fever; indeed, IL6-knockout mice or IL6-neutralizing antibodiesinjected mice were not able to develop LPS-induced fever, even if TNFa and IL1b upregulation was unaltered (Chai et al, 1996;Hamzic et al, 2013;Kozak et al, 1998).…”

Spielen CRP-Spiegel neben IL-6 und PCT noch eine Rolle für Patienten auf Intensivstationen?/Are circulating levels of CRP compared to IL-6 and PCT still relevant in intensive care unit patients?

“…In vivo induziert IL-6 zusammen mit anderen Zytokinen wie TNF oder IL-1 die Akute-Phase-Reaktion und f ü hrt damit unter anderem zur Produktion von Akute Phase Proteinen wie dem CRP [31] .…”

“…Das proinflammatorische Zytokin IL-6 wird von Makrophagen, Lymphozyten sowie endothelialen und mesenchymalen Zellen synthetisiert und ist an der Produktion von Akute-Phase-Proteinen wie dem CRP, beteiligt [31] . Aus diesem Grund ist der IL-6 Anstieg im Blut deutlich fr ü her messbar als der CRP-Anstieg, eine Tatsache, die einen Zeitgewinn in Diagnose und Therapiebeginn erm ö glicht.…”