Kinetics of systemic and intrahypothalamic IL-6 and tumor necrosis factor during endotoxin fever in guinea pigs

Abstract

The time course of activity of interleukin-6 (IL-6) and tumor necrosis factor (TNF) was measured in blood plasma and hypothalamic push-pull perfusates during the febrile response to intramuscular injection of bacterial endotoxin (Escherichia coli, 20 micrograms/kg) in 24 guinea pigs. Injection of endotoxin caused a dramatic increase of IL-6 activity in plasma. The logarithmic values of plasma IL-6 activities showed a linear correlation to the febrile change in body temperature (r = 0.898) during the whole time course of fever. IL-6 activity in hypothalamic perfusates increased 12-fold in the first hour after pyrogen application and declined slowly despite the further increase in body temperature. Hypothalamic IL-6 activity did not correlate with the febrile increase in body temperature (r = -0.048). TNF activity in plasma, not detectable before pyrogen application, had its peak in the first hour after endotoxin injection and rapidly declined to 15-20% of the peak activity within the next 2 h and to an undetectable value 5 h after injection. In the hypothalamus TNF was not detectable before endotoxin injection, but it could be monitored in most animals after pyrogen application without a clear correlation to the fever response. These results taken together indicate that endotoxin fever represents a physiological situation in which production and release of cytokines in the peripheral immune system and in the hypothalamus are regulated and stimulated in independent patterns.

Inhibition of Tumor Necrosis Factor-α Action within the CNS Markedly Reduces the Plasma Adrenocorticotropin Response to Peripheral Local Inflammation in Rats

“…Thus it has been proposed that the changes in CNS function (e.g., fever, sickness, behavior, activation of the HPA axis) during endotoxemia may be attributable to the influence of cytokines generated within the CNS (Kakucska et al, 1993;Klir et al, 1993;Roth et al, 1993;Hopkins and Rothwell, 1995;Laye et al, 1995;Rothwell and Hopkins, 1995). The present study, however, suggests that previous findings of increased cerebral cytokine expression during endotoxemia cannot necessarily be extended to include all peripheral inflammatory insults.…”

Immune-to-brain signaling and central prostaglandin E2synthesis in fasted rats with altered lipopolysaccharide-induced fever

“…An alternative, but not mutually exclusive, explanation is that circulating IL-6, the levels of which were unaffected by fasting, plays a major role in central PGE 2 production. Among the three major pyrogenic cytokines, IL-6 was demonstrated to consistently increase in the circulation after various types of pyrogenic challenges, including LPS, and the circulating levels of this cytokine were shown to correlate with the magnitude of fever more closely to those of TNF and IL-1␤ (1,3,26,30,43). In support of the significant role of this cytokine in the fever response, studies from our laboratory and those of others demonstrated that IL-6 deficiency or anti-IL-6 antiserum treatment strongly attenuates LPS-induced fever (3,4,45).…”

Fever induction pathways: evidence from responses to systemic or local cytokine formation

“…Depending on the route and injected dose of LPS, tumor necrosis factor alpha (TNF-a) is the first cytokine which appears in the circulation (2,5,6), followed by traces of interleukin-1ß (IL-1ß) (5), and high amounts of IL-6 (6,7), IL-8 (8) as well as other cytokines such as, for example, macrophage inflammatory protein-1 (MIP-1) (9). A similar cytokine cascade can be monitored in response to other pyrogenic compounds of Gram-positive and Gram-negative bacteria such as superantigens, peptidoglycans or muramyldipeptides.…”

“…Invading viruses or synthetic viral compounds activate a distinct pattern of cytokine production including interferons as initial mediators within the cytokine cascade (10). Among all cytokines which are measurable in blood plasma during LPS-induced fever, circulating levels of IL-6 show the best correlation with the febrile changes of body temperature (6,7).…”