Production of Systemic and Hypothalamic Cytokines during the Early Phase of Endotoxin Fever

Abstract

Changes in concentrations of cytokines in plasma and in hypothalamic push-pull perfusates of guinea pigs were measured within the 1 st hour after intramuscular injections of bacterial Hpopolysaccharide (LPS; Escherichia coli, 20 µg/kg) or solvent (0.9% saline). In control animals injected with solvent, interleukin (IL)-1 and tumor necrosis factor alpha (TNF-α) were not detectable in plasma. Only IL-6 was present in picogram quantities. Within 45 min after injection of LPS, the concentrations of IL-1, TNF-α, and IL-6 increased in the plasma: by several orders of magnitude for TNF-α and about tenfold for IL-G. Picogram amounts of biologically active IL-1 were detected in plasma after injection of LPS. No steady state levels of systemic cytokines were reached during the experimental period. In hypothalamic perfusates of animals injected with the solvent, no IL-1 was detectable. TNF-α could be detected at higher concentrations than IL-6. IL-6 was detectable at tenfold lower concentrations than in the plasma. In animals injected with LPS, the hypothalamic concentration of IL-6 started to increase during the period 15-30 min and the concentrations of TNF-α during the period 30-45 min after LPS injection. The concentrations of IL-6 increased by 300-400% and did not exceed picogram values. No progressive increase of hypothalamic levels of these cytokines was observed during the time course of the experiment. The method used did not detect any changes in the amount of biologically active IL-1 in hypothalamic perfusates of LPS-treated animals. No obvious correlation between concentrations of cytokines in plasma and hypothalamic perfusate was observed, indicating the brain origin of the cytokines. Since the increase in IL-6 goes in parallel with resetting of the body thermostat to the higher level, the data support the hypothesis that the increase in the concentration of IL-6 in the brain, occurring during the early phase of the fever, induces the febrile response.

Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin

“…These mediators are proinflammatory cytokines that share several biological properties. They normally are practically absent from the nervous system but can become upregulated under neuropathic or inflammatory conditions (Jansky et al, 1995). Complex receptordependent enzymatic signaling cascades have been reported of which only the IL-8 receptor can activate several types of G-protein, including G i (Wu et al, 1993), but none of the known receptors is directly linked to an excitatory ionic current.…”

LPS-activated complement, not LPS per se, triggers the early release of PGE2by Kupffer cells

“…Tumor necrosis factor-␣ (TNF-␣), IL-1␤, and IL-6 are the major cytokines implicated in this response (9). There is, however, a temporal disconnect between the first appearance of these cytokines and the onset of the febrile response to intravenous LPS; that is, fever appears within 10 -15 min (13, 51) whereas TNF-␣, the first cytokine to appear, is not detectable until 30 min after LPS treatment (18,23,24,39). This temporal discrepancy is less evident after the intraperitoneal administration of low to moderate doses of LPS, when the latency of fever onset is ϳ60 min but becomes evident also when higher doses are administered, when the onset latency approaches that after intravenous LPS (7).…”

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.…”