IL-18 Contributes to Bone Cancer Pain by Regulating Glia Cells and Neuron Interaction

Liu, Su; Liu, Yue-peng; Lv, You; Yao, Jun-Li; Yue, Dongmei; Zhang, Mao-yin; Qi, Dashi; Liu, Gongjian

doi:10.1016/j.jpain.2017.10.003

Cited by 41 publications

(32 citation statements)

References 43 publications

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“…In a similar vein, the present study hypothesized the molecular events that microglia-derived IL-18 was regulated via a TLR4/p38 MAPK- IL-18 bound to IL-18R to play a biological role. In line with prior studies [11,14] , we found that elevation of IL-18R induced by IS dural infusions were primarily expressed in astrocytes. IL-18/IL-18R signaling pathway mediated microglia-astrocyte interactions and hence participated in the development of hyperpathia or allodynia induced by IS dural infusions.…”

Section: Discussionsupporting

confidence: 91%

Involvement of Interleukin-18-Mediated Microglia/Astrocyte Interaction in Experimental Models of Migraine

Gong

Lin

et al. 2020

Preprint

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Background: The exact molecular mechanisms of migraine were not fully understood. Emerging evidence indicated that inflammation had a significant role in pathophysiological mechanisms of migraine. The present study aimed to investigate the involvement of Interleukin-18-Mediated Microglia/Astrocyte Interaction in the development of hyperpathia or allodynia induced by migraine. Methods: Experimental rat model of migraine was established by repetitive inflammatory soup (IS) dural infusions. The expression of Interleukin-18 (IL-18) and IL-18 receptor (IL-18R) was examined by quantitative real-time polymerase chain reaction or Western blot. The expression of activated microglia and astrocytes was examined by Western blot or immunofluorescence. The expression of nuclear factor-kappa B (NF-κB) was examined by Western blot. TAK-242 and anti-IL-18 antibody were used to inhibit the activation of toll-like receptor 4 (TLR4) and IL-18 pathway, respectively. Results: IS dural infusions elicited microglial activation and astrocytic activation. Meanwhile, IS dural infusions induced the upregulation of IL-18 and IL-18R in microglia and astrocytes, respectively. Blocking the IL-18 signaling pathway attenuated nociceptive behavior. Meanwhile, blocking IL-18 signaling also suppressed astrocytic activation, as well as activation of NF-κB. And IL-18 dural infusions induced nociceptive behavior and glia activation. Conclusions: IL-18, a product of microglial toll-like receptor 4 (TLR4) activation, acted on IL-18R expressed in astrocyte, and subsequently stimulated activation of NF-κB, leading to the astrocytic activation. Together, the present results suggest that IL-18-mediated microglia/astrocyte interactions in the medullary dorsal horn may participate in the development of hyperpathia or allodynia induced by migraine.

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Section: Discussionsupporting

confidence: 91%

Involvement of Interleukin-18-Mediated Microglia/Astrocyte Interaction in Experimental Models of Migraine

Gong

Lin

et al. 2020

Preprint

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“…IL-18 bound to IL-18R to play a biological role. In line with prior studies [11,14] , we found that elevation of IL-18R induced by IS dural infusions were primarily expressed in astrocytes. IL-18/IL-18R signaling pathway mediated microglia-astrocyte interactions and hence participated in the development of hyperpathia or allodynia induced by IS dural infusions.…”

Section: Discussionsupporting

confidence: 91%

“…Blockage of IL-18 attenuated nociceptive behavior induced by repetitive IS dural infusions and inhibited the activation of NF-κB phosphorylation and astrocyte. IL-18 might activate microglia and astrocytes in an autocrine or paracrine manner, then synthesized and released pro-inflammatory cytokines, neurotransmitters and neuromodulators, amplifying neuronal excitability [4,5,11,14] and inducing migraine attacks. It indicated a new mechanism underlying experimental migraine that IL-18 signaling mediating microglia-astrocyte interactions, contributing to hyperpathia or allodynia induced by IS dural infusions.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Interleukin-18-Mediated Microglia/Astrocyte Interaction in Experimental Models of Migraine

Gong

Lin

Lu³

et al. 2020

Preprint

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Background The exact molecular mechanisms of migraine were not fully understood. Emerging evidence indicated that inflammation had a significant role in pathophysiological mechanisms of migraine. The present study aimed to investigate the role of Interleukin-18-Mediated Microglia/Astrocyte Interaction in the development of hyperpathia or allodynia induced by migraine. Methods Experimental rat model of migraine was established by repetitive inflammatory soup (IS) dural infusions. The expression of Interleukin-18 (IL-18) and IL-18 receptor (IL-18R) was examined by quantitative real-time polymerase chain reaction or Western blot. The expression of activated microglia and astrocytes was examined by Western blot or immunofluorescence. The expression of nuclear factor-kappa B (NF-κB) was examined by Western blot. TAK-242 and anti-IL-18 antibody were used to inhibit the activation of toll-like receptor 4 (TLR4) and IL-18 pathway, respectively. Results IS dural infusions elicited microglial activation and astrocytic activation. Meanwhile, IS dural infusions induced the upregulation of IL-18 and IL-18R in microglia and astrocytes, respectively. Blocking the IL-18 signaling pathway attenuated nociceptive behavior. Meanwhile, blocking IL-18 signaling also suppressed astrocytic activation, as well as activation of NF-κB. And IL-18 dural infusions induced nociceptive behavior and glia activation. Conclusions IL-18, a product of microglial toll-like receptor 4 (TLR4) activation, acted on IL-18R expressed in astrocyte, and subsequently stimulated activation of NF-κB, leading to the astrocytic activation. Together, the present results suggest that IL-18-mediated microglia/astrocyte interactions in the medullary dorsal horn may participate in the development of hyperpathia or allodynia induced by migraine.

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“…Spinal glial activation, mainly the microglia and astrocytes, is now considered as an important factor for the development and maintenance of allodynia and hyperalgesia in various chronic pain models, including inflammatory pain, neuropathic pain, and BCP (Cao et al, 2014;Ni et al, 2016;Jiang et al, 2017;Wang et al, 2018). The activated glial cells contributed to the early development and maintenance of chronic pain by releasing neuromodulators, such as proinflammatory cytokines and chemokines (Miyoshi et al, 2008;Liu et al, 2017). In the present study, BCP induced by intratibial inoculation of Walker 256 cells led to the activation of microglia and astrocytes in the spinal dorsal horn, which was consistent with that of the previous studies (Wang et al, 2011;Hu et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…The activated glial cells promoted pain transmission by releasing neuromodulators, such as chemokines and p r o i n fl a m m a t o r y c y t o k i n e s . T h e e n h a n c e d s p i n a l neuroimmune and neuroinflammatory activities induce and maintain BCP (Shen et al, 2014;Lu et al, 2015;Liu et al, 2017). Mounting evidence suggests that chemokines and proinflammatory cytokines are mainly produced by glial cells in the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

Liquiritin Alleviates Pain Through Inhibiting CXCL1/CXCR2 Signaling Pathway in Bone Cancer Pain Rat

Xie

et al. 2020

Front. Pharmacol.

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Bone cancer pain (BCP) is an intractable clinical problem, and lacked effective drugs for treating it. Recent research showed that several chemokines in the spinal cord are involved in the pathogenesis of BCP. In this study, the antinociceptive effects of liquiritin, which is an active component extracted from Glycyrrhizae Radix, were tested and the underlying mechanisms targeting spinal dorsal horn (SDH) were investigated. The BCP group displayed a significant decrease in the mechanical withdrawal threshold on days 6, 12, and 18 when compared with sham groups. Intrathecal administration of different doses of liquiritin alleviated mechanical allodynia in BCP rats. The results of immunofluorescent staining and western blotting showed that liquiritin inhibited BCPinduced activation of astrocytes in the spinal cord. Moreover, intrathecal administration of liquiritin effectively inhibited the activation of CXCL1/CXCR2 signaling pathway and production of IL-1b and IL-17 in BCP rats. In astroglial-enriched cultures, Lipopolysaccharides (LPS) elicited the release of chemokine CXCL1, and the release was decreased in a dose-dependent manner by liquiritin. In primary neurons, liquiritin indirectly reduced the increase of CXCR2 by astroglial-enriched-conditioned medium but not directly on the CXCR2 target site. These results suggested that liquiritin effectively attenuated BCP in rats by inhibiting the activation of spinal astrocytic CXCL1 and neuronal CXCR2 pathway. These findings provided evidence regarding the the antinociceptive effect of liquiritin on BCP.

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IL-18 Contributes to Bone Cancer Pain by Regulating Glia Cells and Neuron Interaction

Cited by 41 publications

References 43 publications

Involvement of Interleukin-18-Mediated Microglia/Astrocyte Interaction in Experimental Models of Migraine

Involvement of Interleukin-18-Mediated Microglia/Astrocyte Interaction in Experimental Models of Migraine

Involvement of Interleukin-18-Mediated Microglia/Astrocyte Interaction in Experimental Models of Migraine

Liquiritin Alleviates Pain Through Inhibiting CXCL1/CXCR2 Signaling Pathway in Bone Cancer Pain Rat

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