IL-1β Induced Cytokine Expression by Spinal Astrocytes Can Play a Role in the Maintenance of Chronic Inflammatory Pain

Abstract

It is now widely accepted that the glial cells of the central nervous system (CNS) are key players in many processes, especially when they are activated via neuron-glia or glia-glia interactions. In turn, many of the glia-derived pro-inflammatory cytokines contribute to central sensitization during inflammation or nerve injury-evoked pathological pain conditions. The prototype of pro-inflammatory cytokines is interleukin-1beta (IL-1β) which has widespread functions in inflammatory processes. Our earlier findings showed that in the spinal cord (besides neurons) astrocytes express the ligand binding interleukin-1 receptor type 1 (IL-1R1) subunit of the IL-1 receptor in the spinal dorsal horn in the chronic phase of inflammatory pain. Interestingly, spinal astrocytes are also the main source of the IL-1β itself which in turn acts on its neuronal and astrocytic IL-1R1 leading to cell-type specific responses. In the initial experiments we measured the IL-1β concentration in the spinal cord of C57BL/6 mice during the course of complete Freund adjuvant (CFA)-induced inflammatory pain and observed a peak of IL-1β level at the time of highest mechanical sensitivity. In order to further study astrocytic activation, primary astrocyte cultures from spinal cords of C57BL/6 wild type and IL-1R1 deficient mice were exposed to IL-1β in concentrations corresponding to the spinal levels in the CFA-induced pain model. By using cytokine array method we observed significant increase in the expressional level of three cytokines: interleukin-6 (IL-6), granulocyte-macrophage colony stimulating factor (GM-CSF) and chemokine (C-C motif) ligand 5 (CCL5 or RANTES). We also observed that the secretion of the three cytokines is mediated by the NFkB signaling pathway. Our data completes the picture of the IL-1β-triggered cytokine cascade in spinal astrocytes, which may lead to enhanced activation of the local cells (neurons and glia as well) and can lead to the prolonged maintenance of chronic pain. All these cytokines and the NFkB pathway can be possible targets of pain therapy.

Astragalin Inhibits the Proliferation and Migration of Human Colon Cancer HCT116 Cells by Regulating the NF-κB Signaling Pathway

“…IL-6 powerfully stimulating the activation of the JAK/STAT3 pathway to promote tumor proliferation, motility, and invasion ( Yoon et al, 2012 ). IL-1β induced significant upregulation of pro-inflammatory cytokines in astrocytic ( Gajtko et al, 2020 ). TNF-α is a major factor involved in inflammation-associated cancer and plays an important role in the spread and invasion of tumor cells.…”

Calcitonin gene‐related peptide induces the histone H3 lysine 9 acetylation in astrocytes associated with neuroinflammation in rats with neuropathic pain

“…Spinal astrocytes are the main source of the IL‐1β which, in turn, acts on its neuronal and astrocytic IL‐1 receptor (IL‐1R) leading to enhanced activation of the local cells (neurons and glia as well) and can lead to the prolonged maintenance of chronic pain 49 . Despite CX3CR1 is mainly expressed by activated microglia, spinal activated‐astrocytes also express CX3CR1 following injury, 50 consistent with our results that CX3CR1 was increased in cultured astrocytes by HATs following CGRP treatment.…”

“…Remarkably, intrathecal injection of CGRP and CCI resulted in a tremendous increase in the number of astrocytes with H3K9ac expression. Given that astrocytic activation induced by CGRP, as evident by an increased GFAP expression, was found at the same time, it is conceivable that the increased expression of H3K9ac in astrocytes contributes importantly to the astrocytic activation and its production of inflammatory mediators, 49 , 50 which ultimately brings about neuroinflammation in the spinal dorsal horn. In line with our results, recent studies have indicated that several pro‐inflammatory cytokines and chemokines (IL‐1, CXCL12/CXCR4, etc.)…”

The expression and significance of inflammatory cytokines and MMP-9 in the tears of the infected eye and contralateral uninfected eye in patients with fungal keratitis

“…COX-2 and PGE-2 are crucial pain factors. Meanwhile,IL-1β can modulate neuronal intracellular calcium signaling and activates astrocytes ,which can further enhance and prolong neuroin ammation-induced chronic pain [25]. IL-17 can promote astrocyte proliferation and proin ammatory cytokines secretion ,which are related to the neuropathic pain [26].…”