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Red nucleus IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β through the JAK2/STAT3 and ERK signaling pathways.
Neuropathology. 2020 Aug; 40(4):347-357.N

Abstract

We previously reported that interleukin (IL)-6 in the red nucleus (RN) is involved in the maintenance of neuropathic pain induced by spared nerve injury (SNI), and exerts a facilitatory effect via Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and extracellular signal-regulated kinase (ERK) signal transduction pathways. The present study aimed at investigating the roles of tumor necrosis factor-α (TNF-α) and IL-1β in RN IL-6-mediated maintenance of neuropathic pain and related signal transduction pathways. Being similar to the elevation of RN IL-6 three weeks after SNI, increased protein levels of both TNF-α and IL-1β were also observed in the contralateral RN three weeks after the nerve injury. The upregulations of TNF-α and IL-1β were closely correlative with IL-6 and suppressed by intrarubral injection of a neutralizing antibody against IL-6. Administration of either the JAK2 antagonist AG490 or the ERK antagonist PD98059 to the RN of rats with SNI remarkably increased the paw withdrawal threshold (PWT) and inhibited the up-regulations of local TNF-α and IL-1β. Further experiments indicated that intrarubral injection of exogenous IL-6 in naive rats apparently lowered the PWT of the contralateral hindpaw and boosted the local expressions of TNF-α and IL-1β. Pretreatment with AG490 could block IL-6-induced tactile hypersensitivity and suppress the up-regulations of both TNF-α and IL-1β. However, injection of PD98059 in advance only inhibited the upregulation of IL-1β, but not TNF-α. These findings indicate that RN IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β. IL-6 induces the expression of TNF-α through the JAK2/STAT3 pathway, and the production of IL-1β through the JAK2/STAT3 and ERK pathways.

Authors+Show Affiliations

Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, China.Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, China.Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, China.Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, China.Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, China.Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, China.Department of Pathogenic Biology and Immunology, Xi'an Jiaotong University Health Science Center, Xi'an, China.Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32380573

Citation

Yang, Qing-Qing, et al. "Red Nucleus IL-6 Mediates the Maintenance of Neuropathic Pain By Inducing the Productions of TNF-α and IL-1β Through the JAK2/STAT3 and ERK Signaling Pathways." Neuropathology : Official Journal of the Japanese Society of Neuropathology, vol. 40, no. 4, 2020, pp. 347-357.
Yang QQ, Li HN, Zhang ST, et al. Red nucleus IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β through the JAK2/STAT3 and ERK signaling pathways. Neuropathology. 2020;40(4):347-357.
Yang, Q. Q., Li, H. N., Zhang, S. T., Yu, Y. L., Wei, W., Zhang, X., Wang, J. Y., & Zeng, X. Y. (2020). Red nucleus IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β through the JAK2/STAT3 and ERK signaling pathways. Neuropathology : Official Journal of the Japanese Society of Neuropathology, 40(4), 347-357. https://doi.org/10.1111/neup.12653
Yang QQ, et al. Red Nucleus IL-6 Mediates the Maintenance of Neuropathic Pain By Inducing the Productions of TNF-α and IL-1β Through the JAK2/STAT3 and ERK Signaling Pathways. Neuropathology. 2020;40(4):347-357. PubMed PMID: 32380573.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Red nucleus IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β through the JAK2/STAT3 and ERK signaling pathways. AU - Yang,Qing-Qing, AU - Li,Hao-Nan, AU - Zhang,Shu-Ting, AU - Yu,Yan-Li, AU - Wei,Wei, AU - Zhang,Xi, AU - Wang,Jun-Yang, AU - Zeng,Xiao-Yan, Y1 - 2020/05/07/ PY - 2019/12/17/received PY - 2020/02/14/revised PY - 2020/02/21/accepted PY - 2020/5/8/pubmed PY - 2021/8/28/medline PY - 2020/5/8/entrez KW - interleukin-1β KW - interleukin-6 KW - neuropathic pain KW - red nucleus KW - tumor necrosis factor-α SP - 347 EP - 357 JF - Neuropathology : official journal of the Japanese Society of Neuropathology JO - Neuropathology VL - 40 IS - 4 N2 - We previously reported that interleukin (IL)-6 in the red nucleus (RN) is involved in the maintenance of neuropathic pain induced by spared nerve injury (SNI), and exerts a facilitatory effect via Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and extracellular signal-regulated kinase (ERK) signal transduction pathways. The present study aimed at investigating the roles of tumor necrosis factor-α (TNF-α) and IL-1β in RN IL-6-mediated maintenance of neuropathic pain and related signal transduction pathways. Being similar to the elevation of RN IL-6 three weeks after SNI, increased protein levels of both TNF-α and IL-1β were also observed in the contralateral RN three weeks after the nerve injury. The upregulations of TNF-α and IL-1β were closely correlative with IL-6 and suppressed by intrarubral injection of a neutralizing antibody against IL-6. Administration of either the JAK2 antagonist AG490 or the ERK antagonist PD98059 to the RN of rats with SNI remarkably increased the paw withdrawal threshold (PWT) and inhibited the up-regulations of local TNF-α and IL-1β. Further experiments indicated that intrarubral injection of exogenous IL-6 in naive rats apparently lowered the PWT of the contralateral hindpaw and boosted the local expressions of TNF-α and IL-1β. Pretreatment with AG490 could block IL-6-induced tactile hypersensitivity and suppress the up-regulations of both TNF-α and IL-1β. However, injection of PD98059 in advance only inhibited the upregulation of IL-1β, but not TNF-α. These findings indicate that RN IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β. IL-6 induces the expression of TNF-α through the JAK2/STAT3 pathway, and the production of IL-1β through the JAK2/STAT3 and ERK pathways. SN - 1440-1789 UR - https://www.unboundmedicine.com/medline/citation/32380573/Red_nucleus_IL_6_mediates_the_maintenance_of_neuropathic_pain_by_inducing_the_productions_of_TNF_α_and_IL_1β_through_the_JAK2/STAT3_and_ERK_signaling_pathways_ L2 - https://doi.org/10.1111/neup.12653 DB - PRIME DP - Unbound Medicine ER -