Leveraging genetic data to investigate the effects of interleukin-6 receptor signalling on levels of 40 circulating cytokines.

Interleukin 6 (IL-6) is a circulating cytokine implicated in inflammatory processes. However, the broad effects of IL-6 receptor (IL-6R) signalling on other circulating cytokines is not known. Using summary-level data from genome-wide association studies, we leveraged genetic variants that proxy IL-6R signalling in two-sample Mendelian randomization analyses to investigate effects on levels of 40 circulating cytokines. Increased genetically proxied IL-6R signalling was associated with reduced levels of 10 circulating interleukins, chemokines and growth factors. The significant results include IL-10 (Mendelian randomization estimate -0.306, standard error [SE] 0.093), IL-4 (estimate -0.393, SE 0.1007), eotaxin (estimate -0.510, SE 0.1213) and Fibroblast growth factor (estimate -0.334, SE 0.1005). The findings from this study support the feedback effects of IL-6R signalling on reducing levels of some circulating cytokines and identify compensatory mechanisms that maybe modulating its inflammatory effects. These results provide insight into the mechanisms by which IL-6R signalling may be contributing to inflammatory and autoimmune diseases.

Sexual dimorphism in prostacyclin-mimetic responses within rat mesenteric arteries: A novel role for KV 7.1 in shaping IP receptor-mediated relaxation.

BACKGROUND AND PURPOSE: Prostacyclin mimetics express potent vasoactive effects via prostanoid receptors that are not unequivocally defined, as to date no study has considered sex as a factor. The aim of this study was to determine the contribution of IP and EP3 prostanoid receptors to prostacyclin mimetic iloprost-mediated responses, whether KV 7.1-5 channels represent downstream targets of selective prostacyclin-IP-receptor agonist MRE-269 and the impact of the oestrus cycle on vascular reactivity. EXPERIMENTAL APPROACH: Within second-order mesenteric arteries from male and female Wistar rats, we determined (1) relative mRNA transcripts for EP1-4 (Ptger1-4 ), IP (Ptgi) and TXA2 (Tbxa) prostanoid receptors via RT-qPCR; (2) the effect of iloprost, MRE-269, isoprenaline and ML277 on precontracted arterial tone in the presence of inhibitors of prostanoid receptors, potassium channels and the molecular interference of KV 7.1 via wire-myograph; (3) oestrus cycle stage via histological changes in cervical cell preparations. KEY RESULTS: Iloprost evoked a biphasic response in male mesenteric arteries, at concentrations ≤100 nmol·L-1 relaxing, then contracting the vessel at concentration ≥300 nmol·L-1 , a process attributed to IP and EP3 receptors respectively. Secondary contraction was absent in the females, which was associated with a reduction in Ptger3. Pharmacological inhibition and molecular interference of KV 7.1 significantly attenuated relaxations produced by the selective IP receptor agonist MRE-269 in male and female Wistar in dioestrus/metoestrus, but not pro-oestrus/oestrus. CONCLUSIONS AND IMPLICATIONS: Stark sexual dimorphisms in iloprost-mediated vasoactive responses are present within mesenteric arteries. KV 7.1 is implicated in IP receptor-mediated vasorelaxation and is impaired by the oestrus cycle.

Early cognitive development in children born to women with epilepsy: a prospective report.

PURPOSE: In this prospective study the early cognitive development of children born to women with epilepsy (n = 198) was assessed and compared to a group of children representative of the general population (n = 230). METHODS: The children were assessed when younger than the age of 2 years using the Griffiths Mental Development Scales, either in their local participating hospital or in their home. The assessments were completed by an assessor who was blinded to whether the child's mother had epilepsy and to antiepileptic drug type. RESULTS: Children exposed to sodium valproate had a statistically significant increased risk of delayed early development in comparison to the control children. Linear regression analysis showed a statistically significant effect of sodium valproate exposure on the child's overall developmental level that was not accounted for by confounding variables. Delayed early development is also noted for children within an ad hoc group of less commonly utilized antiepileptic drugs, although conclusions cannot be drawn due to the size of this group (n = 13). Children exposed to either carbamazepine or lamotrigine in utero did not differ significantly in their overall developmental ability. Differences noted in specific developmental areas for these two groups were not statistically significant after the control for confounders such as socioeconomic status and maternal IQ. DISCUSSION: Women with epilepsy should be informed of the risks posed to their potential offspring prior to pregnancy to allow for informed decisions regarding treatment. Children exposed in utero to antiepileptic drugs should be monitored throughout childhood to allow for early intervention when necessary.