Spatiotemporal distribution of gp130 cytokines and their receptors after status epilepticus: comparison with neuronal degeneration and microglial activation

Although numerous studies have demonstrated the neurotrophic capacity of gp130 cytokines, it remains unclear whether endogenously expressed cytokines actually function in a direct neuromodulatory manner. Therefore, using the lithium–pilocarpine status epilepticus model, we performed a detailed in situ hybridization time-course study of five gp130 cytokines (interleukin [IL]-6, leukemia inhibitory factor [LIF], IL-11, oncostatin-m [OSM], and ciliary neurotrophic factor), gp130, and the receptors of the cytokines we found to be induced (IL-6 receptor [IL-6R], LIF receptor [LIF-R], and IL-11 receptor [IL-11R]). Additionally, to further understand the regulation of these cytokines, we compared their expression with the pattern of neuronal degeneration and microglial activation. Under control conditions, all cytokines, except LIF, exhibited faint to moderate expression in hippocampal principal layers. After seizure, IL-6, LIF, and IL-11 exhibited a rapid, robust, and transient upregulation in non-principal cells. LIF also exhibited a remarkably early and transient induction in the granule cell layer of the dentate gyrus. OSM exhibited only a mild and inconsistent induction. All receptors examined were strongly expressed only in hippocampal principal layers under control conditions. A mild and late induction of the IL-6R, LIF-R, and IL-11R occurred after seizure with a scattered distribution. A progressive and chronic induction of gp130 was observed in cells that appeared to be associated with blood vessels. Degeneration of hilar interneurons and CA1 pyramidal cells was early and progressive. Granule neurons of the dentate gyrus, however, exhibited a delayed and precipitous pattern of degeneration, specifically in the lateral portion of the superior blade. Microglial activation was maximal 24–48 h post-seizure. We speculate that gp130 cytokines play a paracrine, neuromodulatory role in the hippocampus since both before and after seizure, principal cells appear to be the major cell type expressing the receptors for these cytokines. Furthermore, we suggest that activity-dependent mechanisms may be involved in the regulation of cytokines expressed early, and that relatively late occurring cytokine expression may be elicited by injury-related stimuli.