Red Nucleus Interleukin-6 Evokes Tactile Allodynia in Male Rats Through Modulating Spinal Pro-inflammatory and Anti-inflammatory Cytokines
Our previous studies have clarified that red nucleus (RN) interleukin (IL)-6 is involved in the maintenance of neuropathic pain and produces a facilitatory effect by activating JAK2/STAT3 and ERK pathways. In this study, we further explored the immune molecular mechanisms of rubral IL-6-mediated des...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-04-01
|
| Series: | Frontiers in Molecular Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.820664/full |
| _version_ | 1811285254733824000 |
|---|---|
| author | Qing-Qing Yang Qing-Qing Yang Hao-Nan Li Yu-Tong Xia Xue Tian Fan Feng Jian Yang Ya-Li Xu Juan Guo Xiao-Qi Li Jun-Yang Wang Xiao-Yan Zeng |
| author_facet | Qing-Qing Yang Qing-Qing Yang Hao-Nan Li Yu-Tong Xia Xue Tian Fan Feng Jian Yang Ya-Li Xu Juan Guo Xiao-Qi Li Jun-Yang Wang Xiao-Yan Zeng |
| author_sort | Qing-Qing Yang |
| collection | DOAJ |
| description | Our previous studies have clarified that red nucleus (RN) interleukin (IL)-6 is involved in the maintenance of neuropathic pain and produces a facilitatory effect by activating JAK2/STAT3 and ERK pathways. In this study, we further explored the immune molecular mechanisms of rubral IL-6-mediated descending facilitation at the spinal cord level. IL-6-evoked tactile allodynia was established by injecting recombinant IL-6 into the unilateral RN of naive male rats. Following intrarubral administration of IL-6, obvious tactile allodynia was evoked in the contralateral hindpaw of rats. Meanwhile, the expressions of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 were elevated in the contralateral spinal dorsal horn (L4–L6), blocking spinal TNF-α, IL-1β, or IL-6 with neutralizing antibodies relieved IL-6-evoked tactile allodynia. Conversely, the levels of anti-inflammatory cytokines transforming growth factor-β (TGF-β) and IL-10 were reduced in the contralateral spinal dorsal horn (L4–L6), an intrathecal supplement of exogenous TGF-β, or IL-10 attenuated IL-6-evoked tactile allodynia. Further studies demonstrated that intrarubral pretreatment with JAK2/STAT3 inhibitor AG490 suppressed the elevations of spinal TNF-α, IL-1β, and IL-6 and promoted the expressions of TGF-β and IL-10 in IL-6-evoked tactile allodynia rats. However, intrarubral pretreatment with ERK inhibitor PD98059 only restrained the increase in spinal TNF-α and enhanced the expression of spinal IL-10. These findings imply that rubral IL-6 plays descending facilitation and produces algesic effect through upregulating the expressions of spinal pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 and downregulating the expressions of spinal anti-inflammatory cytokines TGF-β and IL-10 by activating JAK2/STAT3 and/or ERK pathways, which provides potential therapeutic targets for the treatment of pathological pain. |
| first_indexed | 2024-04-13T02:41:28Z |
| format | Article |
| id | doaj.art-a174faf4129548fa8f50bf14e6e4d946 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-13T02:41:28Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-a174faf4129548fa8f50bf14e6e4d9462022-12-22T03:06:11ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-04-011510.3389/fnmol.2022.820664820664Red Nucleus Interleukin-6 Evokes Tactile Allodynia in Male Rats Through Modulating Spinal Pro-inflammatory and Anti-inflammatory CytokinesQing-Qing Yang0Qing-Qing Yang1Hao-Nan Li2Yu-Tong Xia3Xue Tian4Fan Feng5Jian Yang6Ya-Li Xu7Juan Guo8Xiao-Qi Li9Jun-Yang Wang10Xiao-Yan Zeng11Department of Laboratory Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaDepartment of Pathogenic Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, ChinaDepartment of Pathogenic Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, ChinaDepartment of Pathogenic Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, ChinaDepartment of Pathogenic Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, ChinaDepartment of Pathogenic Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, ChinaDepartment of Pathogenic Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, ChinaDepartment of Pathogenic Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, ChinaDepartment of Pathogenic Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, ChinaDepartment of Pathogenic Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, ChinaDepartment of Pathogenic Biology and Immunology, Xi’an Jiaotong University Health Science Center, Xi’an, ChinaDepartment of Laboratory Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaOur previous studies have clarified that red nucleus (RN) interleukin (IL)-6 is involved in the maintenance of neuropathic pain and produces a facilitatory effect by activating JAK2/STAT3 and ERK pathways. In this study, we further explored the immune molecular mechanisms of rubral IL-6-mediated descending facilitation at the spinal cord level. IL-6-evoked tactile allodynia was established by injecting recombinant IL-6 into the unilateral RN of naive male rats. Following intrarubral administration of IL-6, obvious tactile allodynia was evoked in the contralateral hindpaw of rats. Meanwhile, the expressions of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 were elevated in the contralateral spinal dorsal horn (L4–L6), blocking spinal TNF-α, IL-1β, or IL-6 with neutralizing antibodies relieved IL-6-evoked tactile allodynia. Conversely, the levels of anti-inflammatory cytokines transforming growth factor-β (TGF-β) and IL-10 were reduced in the contralateral spinal dorsal horn (L4–L6), an intrathecal supplement of exogenous TGF-β, or IL-10 attenuated IL-6-evoked tactile allodynia. Further studies demonstrated that intrarubral pretreatment with JAK2/STAT3 inhibitor AG490 suppressed the elevations of spinal TNF-α, IL-1β, and IL-6 and promoted the expressions of TGF-β and IL-10 in IL-6-evoked tactile allodynia rats. However, intrarubral pretreatment with ERK inhibitor PD98059 only restrained the increase in spinal TNF-α and enhanced the expression of spinal IL-10. These findings imply that rubral IL-6 plays descending facilitation and produces algesic effect through upregulating the expressions of spinal pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 and downregulating the expressions of spinal anti-inflammatory cytokines TGF-β and IL-10 by activating JAK2/STAT3 and/or ERK pathways, which provides potential therapeutic targets for the treatment of pathological pain.https://www.frontiersin.org/articles/10.3389/fnmol.2022.820664/fullallodyniainterleukin-1βinterleukin-6interleukin-10red nucleusspinal cord |
| spellingShingle | Qing-Qing Yang Qing-Qing Yang Hao-Nan Li Yu-Tong Xia Xue Tian Fan Feng Jian Yang Ya-Li Xu Juan Guo Xiao-Qi Li Jun-Yang Wang Xiao-Yan Zeng Red Nucleus Interleukin-6 Evokes Tactile Allodynia in Male Rats Through Modulating Spinal Pro-inflammatory and Anti-inflammatory Cytokines Frontiers in Molecular Neuroscience allodynia interleukin-1β interleukin-6 interleukin-10 red nucleus spinal cord |
| title | Red Nucleus Interleukin-6 Evokes Tactile Allodynia in Male Rats Through Modulating Spinal Pro-inflammatory and Anti-inflammatory Cytokines |
| title_full | Red Nucleus Interleukin-6 Evokes Tactile Allodynia in Male Rats Through Modulating Spinal Pro-inflammatory and Anti-inflammatory Cytokines |
| title_fullStr | Red Nucleus Interleukin-6 Evokes Tactile Allodynia in Male Rats Through Modulating Spinal Pro-inflammatory and Anti-inflammatory Cytokines |
| title_full_unstemmed | Red Nucleus Interleukin-6 Evokes Tactile Allodynia in Male Rats Through Modulating Spinal Pro-inflammatory and Anti-inflammatory Cytokines |
| title_short | Red Nucleus Interleukin-6 Evokes Tactile Allodynia in Male Rats Through Modulating Spinal Pro-inflammatory and Anti-inflammatory Cytokines |
| title_sort | red nucleus interleukin 6 evokes tactile allodynia in male rats through modulating spinal pro inflammatory and anti inflammatory cytokines |
| topic | allodynia interleukin-1β interleukin-6 interleukin-10 red nucleus spinal cord |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.820664/full |
| work_keys_str_mv | AT qingqingyang rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines AT qingqingyang rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines AT haonanli rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines AT yutongxia rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines AT xuetian rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines AT fanfeng rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines AT jianyang rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines AT yalixu rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines AT juanguo rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines AT xiaoqili rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines AT junyangwang rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines AT xiaoyanzeng rednucleusinterleukin6evokestactileallodyniainmaleratsthroughmodulatingspinalproinflammatoryandantiinflammatorycytokines |