IL‐1β inhibits I_K and increases [Ca²⁺]_i in the carotid body glomus cells and increases carotid sinus nerve firings in the rat

Abstract

Increasing evidence indicates that there exists a reciprocal communication between the immune system and the brain. Interleukin 1beta (IL-1beta), a proinflammatory cytokine produced during immune challenge, is believed to be one of the mediators of immune-to-brain communication, but how it gets into the brain is unknown because of its large molecular weight and difficulty in crossing the blood-brain barrier. Our previous work has demonstrated that IL-1 receptor type I is strongly expressed in the glomus cells of rat carotid body (CB), a well characterized polymodal chemoreceptive organ which serves not only for the detection of hypoxia, hypercapnia and acidity, but also for low temperature and blood glucose. The present study was designed to test whether IL-1beta could stimulate the CB glomus cells and alter the discharge properties in the carotid sinus nerve, the afferent nerve innervating the organ. The results from whole-cell patch-clamp recordings and calcium imaging showed that extracellular application of IL-1beta significantly decreased the outward potassium current and triggered a transient rise in [Ca(2+)](i) in the cultured glomus cells of rat CB. Furthermore, by using extracellular recordings and pharmacological intervention, it was found that IL-1beta stimulation of the CB in the anaesthetized rat in vivo significantly increased the discharge rate in the carotid sinus nerve, most probably mediated by ATP release. This experiment provides evidence that the CB responds to cytokine stimulation and proposes the possibility that the CB might play a role in immune-to-brain communication.

Sustained Exposure to Cytokines and Hypoxia Enhances Excitability of Oxygen-Sensitive Type I Cells in Rat Carotid Body: Correlation with the Expression of HIF-1α Protein and Adrenomedullin

“…Evidence indicates that the signaling pathway for AP-1 involves cell depolarization, Ca 2 + -entry, and the immediate early gene, c-fos (Yuan et al, 2004). Our finding that a cocktail of inflammatory cytokines elevate TH levels are consistent with the recent demonstration that IL-1b, acting via IL-1 receptors on type I cells, evokes depolarization and increased [Ca2 + ] I (Shu et al, 2007;Fan et al, 2009). Our data also show that the effect of cytokines plus hypoxia are additive for expression of HIF-1a and TH, suggesting that these stimuli may act via separate mechanisms that elevate [Ca2 + ] I and/or downstream mediators of gene induction.…”

“…At similar concentrations these agents have been shown to inhibit K + -currents and increase [Ca2 + ] I in type I cells ( Shu et al, 2007;Fan et al, 2009), and enhance gene expression/protein synthesis and/or excitability in cultured sensory neurons ( Binshtok et al, 2008;Melemedjian et al, 2010). The present experiments evaluated the increase in or absence of the cocktail.…”

“…Moreover, acute application of the former cytokine has been shown to inhibit K + -current and elevate [Ca 2 + ] I in type I cells (Shu et al, 2007). The present study extends these important findings by showing for the first time that sustained exposure to inflammatory cytokines increases levels of HIF-1a and the HIF-1-regulated peptide, ADM, suggesting that CH-induced inflammation in carotid body contributes to phenotypic adjustments in type I cells that are associated with chemoreceptor adaptation to hypoxia (Kline et al, 2002a;Martinez et al, 2003).…”

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

“…The regulation of glycine receptor trafficking by Ca 2+ -dependent processes has been described using elegant single particle tracking approaches (10,50,51). IL-1β can rapidly increase intracellular Ca 2+ in astrocytes and neurons (52,53). Combining these observations, we speculate that after IL-1β activates the IL-1R, there is a resulting rise in intracellular Ca 2+ that increases the scaffolding of glycine receptors to gephyrin at synaptic sites.…”

Neural Reflex Control of Inflammation During Sepsis Syndromes

“…Apart from the presence of TNF-α and TNF-R1, it is known that GC from rat CB express IL-1 receptor type I (Wang et al, 2002) and IL-6 receptor α (Wang et al, 2006), and that GC respond to IL-1β application with depolarization and a transient rise in intracellular calcium (Shu et al, 2007). On the other hand, i.p.…”