Abstract
This study was designed to determine the effect of acute caffeine (CAF) administration, which exerts a broad spectrum of anti-inflammatory activity, on the synthesis of pro-inflammatory cytokines and their receptors in the hypothalamus and choroid plexus (ChP) during acute inflammation caused by the injection of bacterial endotoxin—lipopolysaccharide (LPS). The experiment was performed on 24 female sheep randomly divided into four groups: control; LPS treated (iv.; 400 ng/kg of body mass (bm.)); CAF treated (iv.; 30 mg/kg of bm.); and LPS and CAF treated. The animals were euthanized 3 h after the treatment. It was found that acute administration of CAF suppressed the synthesis of interleukin (IL-1β) and tumor necrosis factor (TNF)α, but did not influence IL-6, in the hypothalamus during LPS-induced inflammation. The injection of CAF reduced the LPS-induced expression of TNF mRNA in the ChP. CAF lowered the gene expression of IL-6 cytokine family signal transducer (IL6ST) and TNF receptor superfamily member 1A (TNFRSF1) in the hypothalamus and IL-1 type II receptor (IL1R2) in the ChP. Our study on the sheep model suggests that CAF may attenuate the inflammatory response at the hypothalamic level and partly influence the inflammatory signal generated by the ChP cells. This suggests the potential of CAF to suppress neuroinflammatory processes induced by peripheral immune/inflammatory challenges.
Highlights
The inflammation caused by a bacterial or viral infection often influences the activity of neurons located in different hypothalamic nuclei that centrally regulate thermogenesis, food intake, reproduction, and circadian rhythms of rest-activity and sleep [1,2,3,4]
With the use of the female sheep model, which exhibits similar sensitivity to LPS [39] and has a diurnal activity pattern as humans [40], we evaluated the effect of acute administration of CAF on the expression of pro-inflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor (TNF)-α) and their receptors (IL-1 receptor type I—IL1R1 and type II—IL1R2, IL-6 receptor—IL6R and signal-transducing component—IL-6 cytokine family signal transducer (IL6ST), TNFα receptor type I—TNFRSF1A and type II—TNFRSF1B) in the hypothalamus and choroid plexus (ChP) during an immune/inflammatory challenge induced in the follicular phase of the estrous cycle
The single injection of LPS affected (p < 0.05) the expression of all examined pro-inflammatory cytokines: IL-1β, IL-6, and TNFα, as indicated by higher (p < 0.05) mRNA expression together with an increase (p < 0.05) of cytokines concentration in the LPS/C group compared to the control (Figure 1A–C with inserts)
Summary
The inflammation caused by a bacterial or viral infection often influences the activity of neurons located in different hypothalamic nuclei that centrally regulate thermogenesis, food intake, reproduction, and circadian rhythms of rest-activity and sleep [1,2,3,4]. Bacterial endotoxins have been observed to disturb the mechanism regulating reproductive processes in cows [5], sheep [6], pigs [7], rats [8], and non-human primates [9]. Studies on rats and sheep models indicated that both systemic LPS treatment and central administration of IL-1β, and TNFα into the region of the hypothalamus suppress the secretion of the gonadotropin-releasing hormone leading to downstream inhibition of the hypothalamic-pituitary-gonadal axis (HPG axis), the main neuroendocrine axis regulating reproduction [13,16,17,18]. Pharmacological inhibition of the synthesis of pro-inflammatory cytokines in the hypothalamus during endotoxin-induced immune challenge has been shown to reduce the inhibitory effect of inflammation on the activity of the HPG axis in sheep during the follicular phase [19]
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