{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:06:41Z","timestamp":1790312801193,"version":"4.1.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2022,7,16]],"date-time":"2022-07-16T00:00:00Z","timestamp":1657929600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,16]],"date-time":"2022-07-16T00:00:00Z","timestamp":1657929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurochem Res"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) possesses potent anti-inflammatory effect. However, if TIPE2 ameliorates sciatic nerve injury (SNI)-induced inflammation and pain remains undiscussed, and the underlying role TAK1 in it were unknown. To verify our imagine, we performed SNI surgery, and analyzed expression and colocalization of TIPE2 and TAK1 in spinal cord and dorsal root neurons (DRG) by immunofluorescence staining and western blot. And the biological analysis, inflammatory factors, and pathological improvement were determined, and the regulation of TIPE2 in TAK1, phosphor-NF-\u03baB, phospho-JNK was also tested by immunofluorescence staining and western blot. Experimental results showed the parabola-like change of TIPE2 and rising expression of TAK1 in spinal cord and DRG. And intrathecal TIPE2 injection could significantly improve the status of SNI rats, inhibit level of IL-6, IL-10 and TNF-\u03b1, raise the thermal withdrawal relax latency and mechanical withdrawal thresholds. Meanwhile, we also detected how TIPE2 regulated TAK1, and the downstream pathway NF-\u03baB and JNK. The result indicated that TIPE2 could reduce TAK1 expression, and make NF-\u03baB and JNK inactivated. To deeply discuss the potential mechanism, we injected TAK1 oligodeoxynucleotide into rats, and found that TIPE2 exerted the protective role against SNI through TAK1. In brief, TIPE2 reduced expression of TAK1, thereby inhibiting activation of NF-kB and JNK, further improving the neuroinflammation and neuropathic pain. TIPE2 played a protective role in sciatic nerve injury rats through regulating TAK1.<\/jats:p>","DOI":"10.1007\/s11064-022-03671-4","type":"journal-article","created":{"date-parts":[[2022,7,16]],"date-time":"2022-07-16T18:02:26Z","timestamp":1657994546000},"page":"3167-3177","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Exogenous TIPE2 Inhibit TAK1 to Improve Inflammation and Neuropathic Pain Induced by Sciatic Nerve Injury Through Inactivating NF-\u03baB and JNK"],"prefix":"10.1007","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6127-713X","authenticated-orcid":false,"given":"Xuehua","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyou","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youfei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,16]]},"reference":[{"issue":"2","key":"3671_CR1","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.expneurol.2011.08.018","volume":"234","author":"M Calvo","year":"2012","unstructured":"Calvo M, Bennett DL (2012) The mechanisms of microgliosis and pain following peripheral nerve injury. Exp Neurol 234(2):271\u2013282. https:\/\/doi.org\/10.1016\/j.expneurol.2011.08.018","journal-title":"Exp Neurol"},{"key":"3671_CR2","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/b978-0-12-420045-6.00008-0","volume":"109","author":"P Tos","year":"2013","unstructured":"Tos P, Ronchi G, Geuna S et al (2013) Future perspectives in nerve repair and regeneration. Int Rev Neurobiol 109:165\u2013192. https:\/\/doi.org\/10.1016\/b978-0-12-420045-6.00008-0","journal-title":"Int Rev Neurobiol"},{"issue":"1","key":"3671_CR3","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3171\/jns.1991.75.1.0015","volume":"75","author":"CH Tator","year":"1991","unstructured":"Tator CH, Fehlings MG (1991) Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg 75(1):15\u201326. https:\/\/doi.org\/10.3171\/jns.1991.75.1.0015","journal-title":"J Neurosurg"},{"issue":"24","key":"3671_CR4","doi-asserted-by":"publisher","first-page":"1967","DOI":"10.1089\/neu.2013.3223","volume":"31","author":"D Umebayashi","year":"2014","unstructured":"Umebayashi D, Natsume A, Takeuchi H et al (2014) Blockade of gap junction hemichannel protects secondary spinal cord injury from activated microglia-mediated glutamate exitoneurotoxicity. J Neurotrauma 31(24):1967\u20131974. https:\/\/doi.org\/10.1089\/neu.2013.3223","journal-title":"J Neurotrauma"},{"key":"3671_CR5","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.pneurobio.2015.09.003","volume":"144","author":"A Verkhratsky","year":"2016","unstructured":"Verkhratsky A, Steardo L, Parpura V et al (2016) Translational potential of astrocytes in brain disorders. Prog Neurobiol 144:188\u2013205. https:\/\/doi.org\/10.1016\/j.pneurobio.2015.09.003","journal-title":"Prog Neurobiol"},{"issue":"9","key":"3671_CR6","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1016\/j.it.2020.07.007","volume":"41","author":"F Giovannoni","year":"2020","unstructured":"Giovannoni F, Quintana FJ (2020) The role of astrocytes in CNS inflammation. Trends Immunol 41(9):805\u2013819. https:\/\/doi.org\/10.1016\/j.it.2020.07.007","journal-title":"Trends Immunol"},{"issue":"9","key":"3671_CR7","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1016\/j.it.2016.06.006","volume":"37","author":"E Colombo","year":"2016","unstructured":"Colombo E, Farina C (2016) Astrocytes: key regulators of neuroinflammation. Trends Immunol 37(9):608\u2013620. https:\/\/doi.org\/10.1016\/j.it.2016.06.006","journal-title":"Trends Immunol"},{"key":"3671_CR8","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/978-3-662-46450-2_8","volume":"227","author":"EA Old","year":"2015","unstructured":"Old EA, Clark AK, Malcangio M (2015) The role of glia in the spinal cord in neuropathic and inflammatory pain. Handb Exp Pharmacol 227:145\u2013170. https:\/\/doi.org\/10.1007\/978-3-662-46450-2_8","journal-title":"Handb Exp Pharmacol"},{"issue":"8","key":"3671_CR9","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/s0166-2236(00)01854-3","volume":"24","author":"LR Watkins","year":"2001","unstructured":"Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24(8):450\u2013455. https:\/\/doi.org\/10.1016\/s0166-2236(00)01854-3","journal-title":"Trends Neurosci"},{"issue":"3","key":"3671_CR10","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/j.pain.2010.01.001","volume":"148","author":"ES Fu","year":"2010","unstructured":"Fu ES, Zhang YP, Sagen J et al (2010) Transgenic inhibition of glial NF-kappa B reduces pain behavior and inflammation after peripheral nerve injury. Pain 148(3):509\u2013518. https:\/\/doi.org\/10.1016\/j.pain.2010.01.001","journal-title":"Pain"},{"issue":"5244","key":"3671_CR11","doi-asserted-by":"publisher","first-page":"2008","DOI":"10.1126\/science.270.5244.2008","volume":"270","author":"K Yamaguchi","year":"1995","unstructured":"Yamaguchi K, Shirakabe K, Shibuya H et al (1995) Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 270(5244):2008\u20132011. https:\/\/doi.org\/10.1126\/science.270.5244.2008","journal-title":"Science"},{"issue":"1","key":"3671_CR12","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s12964-020-00556-3","volume":"18","author":"WL Dai","year":"2020","unstructured":"Dai WL, Yan B, Bao YN et al (2020) Suppression of peripheral NGF attenuates neuropathic pain induced by chronic constriction injury through the TAK1-MAPK\/NF-\u03baB signaling pathways. Cell Commun Signal 18(1):66. https:\/\/doi.org\/10.1186\/s12964-020-00556-3","journal-title":"Cell Commun Signal"},{"issue":"7","key":"3671_CR13","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1002\/glia.20648","volume":"56","author":"H Katsura","year":"2008","unstructured":"Katsura H, Obata K, Miyoshi K et al (2008) Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury. Glia 56(7):723\u2013733. https:\/\/doi.org\/10.1002\/glia.20648","journal-title":"Glia"},{"issue":"43","key":"3671_CR14","doi-asserted-by":"publisher","first-page":"22650","DOI":"10.1074\/jbc.M116.733451","volume":"291","author":"M Oho","year":"2016","unstructured":"Oho M, Nakano R, Nakayama R et al (2016) TIPE2 (tumor necrosis factor \u03b1-induced protein 8-like 2) is a novel negative regulator of TAK1 signal. J Biol Chem 291(43):22650\u201322660. https:\/\/doi.org\/10.1074\/jbc.M116.733451","journal-title":"J Biol Chem"},{"issue":"9","key":"3671_CR15","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1007\/s00109-015-1288-9","volume":"93","author":"H Zhang","year":"2015","unstructured":"Zhang H, Zhu T, Liu W et al (2015) TIPE2 acts as a negative regulator linking NOD2 and inflammatory responses in myocardial ischemia\/reperfusion injury. J Mol Med (Berl) 93(9):1033\u20131043. https:\/\/doi.org\/10.1007\/s00109-015-1288-9","journal-title":"J Mol Med (Berl)"},{"issue":"3","key":"3671_CR16","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.cell.2008.03.026","volume":"133","author":"H Sun","year":"2008","unstructured":"Sun H, Gong S, Carmody RJ et al (2008) TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell 133(3):415\u2013426. https:\/\/doi.org\/10.1016\/j.cell.2008.03.026","journal-title":"Cell"},{"issue":"1\u20132","key":"3671_CR17","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/s0165-5728(02)00366-1","volume":"133","author":"RJ Carmody","year":"2002","unstructured":"Carmody RJ, Hilliard B, Maguschak K et al (2002) Genomic scale profiling of autoimmune inflammation in the central nervous system: the nervous response to inflammation. J Neuroimmunol 133(1\u20132):95\u2013107. https:\/\/doi.org\/10.1016\/s0165-5728(02)00366-1","journal-title":"J Neuroimmunol"},{"issue":"1","key":"3671_CR18","doi-asserted-by":"publisher","first-page":"112631","DOI":"10.1016\/j.yexcr.2021.112631","volume":"404","author":"X Sun","year":"2021","unstructured":"Sun X, Li X, Zhou Y et al (2021) Up-regulating TIPE2 alleviates inflammatory pain by suppressing microglial activation-mediated inflammatory response via inhibiting Rac1\/NF-\u03baB pathway. Exp Cell Res 404(1):112631. https:\/\/doi.org\/10.1016\/j.yexcr.2021.112631","journal-title":"Exp Cell Res"},{"issue":"39","key":"3671_CR19","doi-asserted-by":"publisher","first-page":"32546","DOI":"10.1074\/jbc.M112.348755","volume":"287","author":"Y Zhang","year":"2012","unstructured":"Zhang Y, Wei X, Liu L et al (2012) TIPE2, a novel regulator of immunity, protects against experimental stroke. J Biol Chem 287(39):32546\u201332555. https:\/\/doi.org\/10.1074\/jbc.M112.348755","journal-title":"J Biol Chem"},{"issue":"13","key":"3671_CR20","doi-asserted-by":"publisher","first-page":"4891","DOI":"10.1523\/jneurosci.21-13-04891.2001","volume":"21","author":"T Fukuoka","year":"2001","unstructured":"Fukuoka T, Kondo E, Dai Y et al (2001) Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model. J Neurosci 21(13):4891\u20134900. https:\/\/doi.org\/10.1523\/jneurosci.21-13-04891.2001","journal-title":"J Neurosci"},{"key":"3671_CR21","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.neulet.2014.02.065","volume":"566","author":"H Yu","year":"2014","unstructured":"Yu H, Liu J, Ma J et al (2014) Local delivery of controlled released nerve growth factor promotes sciatic nerve regeneration after crush injury. Neurosci Lett 566:177\u2013181. https:\/\/doi.org\/10.1016\/j.neulet.2014.02.065","journal-title":"Neurosci Lett"},{"key":"3671_CR22","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.neulet.2013.04.054","volume":"547","author":"J Ma","year":"2013","unstructured":"Ma J, Liu J, Yu H et al (2013) Curcumin promotes nerve regeneration and functional recovery in rat model of nerve crush injury. Neurosci Lett 547:26\u201331. https:\/\/doi.org\/10.1016\/j.neulet.2013.04.054","journal-title":"Neurosci Lett"},{"issue":"14","key":"3671_CR23","doi-asserted-by":"publisher","first-page":"e2000096","DOI":"10.1002\/mnfr.202000096","volume":"64","author":"H Guan","year":"2020","unstructured":"Guan H, Li J, Tan X et al (2020) Natural xanthone \u03b1-mangostin inhibits LPS-induced microglial inflammatory responses and memory impairment by blocking the TAK1\/NF-\u03baB signaling pathway. Mol Nutr Food Res 64(14):e2000096. https:\/\/doi.org\/10.1002\/mnfr.202000096","journal-title":"Mol Nutr Food Res"},{"issue":"1","key":"3671_CR24","doi-asserted-by":"publisher","first-page":"259","DOI":"10.4049\/jimmunol.1900083","volume":"203","author":"CQ Lei","year":"2019","unstructured":"Lei CQ, Wu X, Zhong X et al (2019) USP19 inhibits TNF-\u03b1- and IL-1\u03b2-triggered NF-\u03baB activation by deubiquitinating TAK1. J Immunol 203(1):259\u2013268. https:\/\/doi.org\/10.4049\/jimmunol.1900083","journal-title":"J Immunol"},{"key":"3671_CR25","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.intimp.2016.04.039","volume":"36","author":"X Li","year":"2016","unstructured":"Li X, Jin Q, Wu YL et al (2016) Tetrandrine regulates hepatic stellate cell activation via TAK1 and NF-\u03baB signaling. Int Immunopharmacol 36:263\u2013270. https:\/\/doi.org\/10.1016\/j.intimp.2016.04.039","journal-title":"Int Immunopharmacol"},{"issue":"6724","key":"3671_CR26","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/18465","volume":"398","author":"J Ninomiya-Tsuji","year":"1999","unstructured":"Ninomiya-Tsuji J, Kishimoto K, Hiyama A et al (1999) The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398(6724):252\u2013256. https:\/\/doi.org\/10.1038\/18465","journal-title":"Nature"},{"issue":"2","key":"3671_CR27","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1006\/dbio.2001.0338","volume":"236","author":"M Goswami","year":"2001","unstructured":"Goswami M, Uzgare AR, Sater AK (2001) Regulation of MAP kinase by the BMP-4\/TAK1 pathway in Xenopus ectoderm. Dev Biol 236(2):259\u2013270. https:\/\/doi.org\/10.1006\/dbio.2001.0338","journal-title":"Dev Biol"},{"issue":"24","key":"3671_CR28","doi-asserted-by":"publisher","first-page":"2852","DOI":"10.4161\/cc.5.24.3558","volume":"5","author":"JR Delaney","year":"2006","unstructured":"Delaney JR, Mlodzik M (2006) TGF-beta activated kinase-1: new insights into the diverse roles of TAK1 in development and immunity. Cell Cycle 5(24):2852\u20132855. https:\/\/doi.org\/10.4161\/cc.5.24.3558","journal-title":"Cell Cycle"},{"issue":"10","key":"3671_CR29","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1016\/j.tips.2012.06.007","volume":"33","author":"H Sakurai","year":"2012","unstructured":"Sakurai H (2012) Targeting of TAK1 in inflammatory disorders and cancer. Trends Pharmacol Sci 33(10):522\u2013530. https:\/\/doi.org\/10.1016\/j.tips.2012.06.007","journal-title":"Trends Pharmacol Sci"},{"issue":"22","key":"3671_CR30","doi-asserted-by":"publisher","first-page":"2668","DOI":"10.1101\/gad.1360605","volume":"19","author":"JH Shim","year":"2005","unstructured":"Shim JH, Xiao C, Paschal AE et al (2005) TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 19(22):2668\u20132681. https:\/\/doi.org\/10.1101\/gad.1360605","journal-title":"Genes Dev"}],"container-title":["Neurochemical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11064-022-03671-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11064-022-03671-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11064-022-03671-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T09:17:49Z","timestamp":1663060669000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11064-022-03671-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,16]]},"references-count":30,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2022,10]]}},"alternative-id":["3671"],"URL":"https:\/\/doi.org\/10.1007\/s11064-022-03671-4","relation":{},"ISSN":["0364-3190","1573-6903"],"issn-type":[{"value":"0364-3190","type":"print"},{"value":"1573-6903","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,16]]},"assertion":[{"value":"24 January 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 June 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 June 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no relevant financial or non-financial interests to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of\u00a0Yantai Affiliated Hospital of Binzhou Medical University.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval"}}]}}