Expression of the Interleukin 6 System in Cortical Lesions From Patients With Tuberous Sclerosis Complex and Focal Cortical Dysplasia Type IIb

Abstract

Tuberous sclerosis complex (TSC) and focal cortical dysplasia type IIb (FCDIIb) are characterized by epilepsy-associated cerebral cortical malformations. To understand the potential role of the inflammatory cytokine interleukin 6 (IL-6) in the pathogenesis of these lesions, we analyzed the IL-6 system in TSC and FCDIIb cortical lesions and in control cortex (CTX). Greater messenger RNA and protein levels of IL-6 and of its receptors (i.e. IL-6 receptor [IL-6R] and glycoprotein 130 [gp130]) were observed in TSC and FCDIIb lesions versus CTX. Immunohistochemical analyses indicated that IL-6 and IL-6R were strongly expressed in misshapen cells, namely, dysmorphic neurons, giant neurons, and balloon cells. Glycoprotein 130 was diffusely expressed in nearly all cell types. Most IL-6/IL-6R+ misshapen cells colabeled with neuronal rather than astrocytic markers, suggesting a neuronal lineage; most IL-6/IL-6R+ balloon cells in FCDIIb expressed glial fibrillary acidic protein. Protein levels of Janus kinase 2 and phosphorylated signal transducer and activator of transcription 3 were greater than in CTX, suggesting involvement of the gp130-Janus kinase 2-signal transducer and activator of transcription 3 pathway in IL-6 signal transduction. Soluble IL-6R, but not soluble gp130, was greater in TSC and FCDIIb lesions than in CTX, indicating activation of this trans-signaling pathway. These results suggest that overexpression in the IL-6 system and activation of IL-6 signal transduction pathways may contribute to the pathogenesis of cortical lesions in TSC and FCDIIb.

Increased Expression of TRPC5 in Cortical Lesions of the Focal Cortical Dysplasia

“…It is that the persistent neuronal upregulation of TRPC5 in BCs of human FCD tissue influence the neurite growth and then disrupt the normal neuronal circuitry, and finally contribute to epileptogenesis. In addition, consistent with the previous studies (He et al 2013;Shu et al 2010;Oh et al 2008), immunohistochemistry analyses showed that BCs labeled with both the neuronal marker NeuN and glial marker GFAP, suggesting that they could be both neuronal and glial lineages. Oh et al suggested that the BCs are incompletely matured cells of glial or neuronal lineage and that they are formed by the abnormal morphologic differentiation of neural stem cells during early neural development (Oh et al 2008).…”

TLR1 expression in mouse brain was increased in a KA-induced seizure model

“…Total RNA samples (n = 8 each subunit) were isolated from the hippocampus and temporal cortex using an RNA extraction method that has been previously described [6]. The quality and quantity of the final RNA were determined with a NanoDrop 2000 Spectrophotometer (Thermo Scientific, Wilmington, DE, USA) and were verified by agarose gel electrophoresis.…”

“…As in our previous report [6], protein extraction from the hippocampus and temporal cortex was performed according to the manufacturer's protocol (Biyuntian Technologic Inc., China). Tissue homogenates were lysed in RIPA buffer containing 1 9 phosphate-buffered saline (PBS), 1 % IGEPAL CA-630, 0.5 % sodium deoxycholate, 0.1 % sodium dodecyl sulfate, and 10 % protease inhibitor cocktail (Sigma, St Louis, MO, USA).…”

“…Several inflammatory mediators, such as IL-17, IL-2, IL-6, and IL-1, have been detected in surgically resected brain tissue from patients with refractory TLE and cortical dysplasia-related epilepsy [5][6][7][8]. Inflammation in tissue from patients with epilepsy is largely induced by the Toll-like receptors (TLRs).…”

The Effects of Vagus Nerve Stimulation on Pro- and Anti-Inflammatory Cytokines in Children with Refractory Epilepsy: An Exploratory Study

“…Furthermore, we aimed to determine if the changes in cytokine levels could predict the clinical response. Therefore, we determined levels of interleukin (IL)-1β and IL-6, while these cytokines were increased in epilepsy patients [21,22,23,24,25,26]. Additionally, we also evaluated levels of IL-10, as this is one of the most important anti-inflammatory cytokines [27].…”