Skip to main content
SpringerLink
Log in

JAB1 is Involved in Neuropathic Pain by Regulating JNK and NF-κB Activation After Chronic Constriction Injury

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Neuropathic pain, caused by a lesion or dysfunction of the somatosensory nervous system, is a severe debilitating condition with which clinical treatment remains challenging. Jun activation domain-binding protein (JAB1) is a multifunctional protein that participates in several signaling pathways, controlling cell proliferation and apoptosis. However, the expression and possible function of JAB1 in the pathogenesis of neuropathic pain has not been elucidated. This study aimed to investigate the possible involvement of JAB1. Here, employing a neuropathic pain model induced by chronic constriction injury (CCI) on rats, we reported the role of JAB1 in the maintenance of neuropathic pain. By western blot, we found that CCI markedly up-regulated JAB1 expression in the dorsal root ganglion (DRG) and spinal cord. Immunofluorescent assay demonstrated that JAB1 was extensively localized in IB4-, CGRP- and NF200-positive neurons in the injured L5 DRG, and mainly co-localized with NeuN in spinal cord. In addition, we showed that CCI induced phosphorylation of p65 and JNK in vivo. Intrathecal injection of JAB1 siRNA significantly attenuated the CCI-induced JNK and p65 phosphorylation and alleviated both mechanical allodynia and heat hyperalgesia in rats. Taken together, these results suggested that JAB1 promotes neuropathic pain via positively regulating JNK and NF-κB activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J (2008) Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70:1630–1635

    Article  CAS  PubMed  Google Scholar 

  2. Woolf CJ, Mannion RJ (1999) Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353:1959–1964

    Article  CAS  PubMed  Google Scholar 

  3. Baron R (2006) Mechanisms of disease: neuropathic pain—a clinical perspective. Nat Clin Pract Neurol 2:95–106

    Article  PubMed  Google Scholar 

  4. Costigan M, Scholz J, Woolf CJ (2009) Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 32:1–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wei N, Deng XW (2003) The COP9 signalosome. Annu Rev Cell Dev Biol 19:261–286

    Article  CAS  PubMed  Google Scholar 

  6. Huang X, Hetfeld BK, Seifert U, Kahne T, Kloetzel PM, Naumann M, Bech-Otschir D, Dubiel W (2005) Consequences of COP9 signalosome and 26S proteasome interaction. FEBS J 272:3909–3917

    Article  CAS  PubMed  Google Scholar 

  7. Chang EC, Schwechheimer C (2004) ZOMES III: the interface between signalling and proteolysis. Meeting on the COP9 signalosome, proteasome and eIF3. EMBO Rep 5:1041–1045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang J, Li C, Liu Y, Mei W, Yu S, Liu C, Zhang L, Cao X, Kimberly RP, Grizzle W, Zhang HG (2006) JAB1 determines the response of rheumatoid arthritis synovial fibroblasts to tumor necrosis factor-alpha. Am J Pathol 169:889–902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bae MK, Ahn MY, Jeong JW, Bae MH, Lee YM, Bae SK, Park JW, Kim KR, Kim KW (2002) Jab1 interacts directly with HIF-1alpha and regulates its stability. J Biol Chem 277:9–12

    Article  CAS  PubMed  Google Scholar 

  10. Boussiotis VA, Freeman GJ, Taylor PA, Berezovskaya A, Grass I, Blazar BR, Nadler LM (2000) p27kip1 functions as an anergy factor inhibiting interleukin 2 transcription and clonal expansion of alloreactive human and mouse helper T lymphocytes. Nat Med 6:290–297

    Article  CAS  PubMed  Google Scholar 

  11. Lyapina S, Cope G, Shevchenko A, Serino G, Tsuge T, Zhou C, Wolf DA, Wei N, Shevchenko A, Deshaies RJ (2001) Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome. Science 292:1382–1385

    Article  CAS  PubMed  Google Scholar 

  12. Bech-Otschir D, Kraft R, Huang X, Henklein P, Kapelari B, Pollmann C, Dubiel W (2001) COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system. EMBO J 20:1630–1639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cheng X, Zhou Z, Xu G, Zhao J, Wu H, Long L, Wen H, Gu X, Wang Y (2013) Dynamic changes of Jab1 and p27kip1 expression in injured rat sciatic nerve. J Mol Neurosci 51:148–158

    Article  CAS  PubMed  Google Scholar 

  14. Guo CJ, Douglas SD, Gao Z, Wolf BA, Grinspan J, Lai JP, Riedel E, Ho WZ (2004) Interleukin-1beta upregulates functional expression of neurokinin-1 receptor (NK-1R) via NF-κB in astrocytes. Glia 48:259–266

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kim HK, Park SK, Zhou JL, Taglialatela G, Chung K, Coggeshall RE, Chung JM (2004) Reactive oxygen species (ROS) play an important role in a rat model of neuropathic pain. Pain 111:116–124

    Article  CAS  PubMed  Google Scholar 

  16. Sakaue G, Shimaoka M, Fukuoka T, Hiroi T, Inoue T, Hashimoto N, Sakaguchi T, Sawa Y, Morishita R, Kiyono H, Noguchi K, Mashimo T (2001) NF-κB decoy suppresses cytokine expression and thermal hyperalgesia in a rat neuropathic pain model. NeuroReport 12:2079–2084

    Article  CAS  PubMed  Google Scholar 

  17. Xu YQ, Jin SJ, Liu N, Li YX, Zheng J, Ma L, Du J, Zhou R, Zhao CJ, Niu Y, Sun T, Yu JQ (2014) Aloperine attenuated neuropathic pain induced by chronic constriction injury via anti-oxidation activity and suppression of the nuclear factor kappa B pathway. Biochem Biophys Res Commun 451:568–573

    Article  CAS  PubMed  Google Scholar 

  18. Pan YD, Guo QL, Wang E, Ye Z, He ZH, Zou WY, Cheng ZG, Wang YJ (2010) Intrathecal infusion of pyrrolidine dithiocarbamate for the prevention and reversal of neuropathic pain in rats using a sciatic chronic constriction injury model. Reg Anesth Pain Med 35:231–237

    Article  PubMed  Google Scholar 

  19. Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR (2006) A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 26:3551–3560

    Article  CAS  PubMed  Google Scholar 

  20. Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Decosterd I (2006) Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol 2:259–269

    Article  PubMed  PubMed Central  Google Scholar 

  21. Obata K, Noguchi K (2004) MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci 74:2643–2653

    Article  CAS  PubMed  Google Scholar 

  22. Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110

    Article  CAS  PubMed  Google Scholar 

  23. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63

    Article  CAS  PubMed  Google Scholar 

  24. Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 67:313–316

    Article  CAS  PubMed  Google Scholar 

  25. Jensen TS, Baron R, Haanpaa M, Kalso E, Loeser JD, Rice AS, Treede RD (2011) A new definition of neuropathic pain. Pain 152:2204–2205

    Article  PubMed  Google Scholar 

  26. von Hehn CA, Baron R, Woolf CJ (2012) Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 73:638–652

    Article  Google Scholar 

  27. Pollock J, McFarlane SM, Connell MC, Zehavi U, Vandenabeele P, MacEwan DJ, Scott RH (2002) TNF-alpha receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones. Neuropharmacology 42:93–106

    Article  CAS  PubMed  Google Scholar 

  28. Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B, Davis RJ (1996) Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J 15:2760–2770

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Gao YJ, Ji RR (2008) Activation of JNK pathway in persistent pain. Neurosci Lett 437:180–183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work were supported by National Basic Research Program of China (973 Program, No. 2012CB822104); National Natural Science Foundation of China (31500647, 31170766); the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (15KJA310003); the Natural Science Foundation of Jiangsu Province (BK20150408); the Six Talent Peaks Project in Jiangsu Province (YY-050); A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Author information

Author notes

    Authors and Affiliations

    1. Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, 226001, China

      Yan Chen, Xingguo Xu, Xiaojia Wei, Xiaoling Gu & Zhongling Xu

    2. Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, China

      Yan Chen, Xiaojia Wei, Xiaoling Gu, Dongmei Zhang & Zhongling Xu

    3. Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, 226001, China

      Xiangdong Chen & Jiang Yu

    4. Laboratory Animal Center, Nantong University, Nantong, 226001, China

      Chun Liu

    5. Department of Pathogen Biology, Medical College, Nantong University, Nantong, 226001, China

      Dongmei Zhang

    Authors
    1. Yan Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Xiangdong Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jiang Yu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Xingguo Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Xiaojia Wei
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Xiaoling Gu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Chun Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Dongmei Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Zhongling Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Dongmei Zhang or Zhongling Xu.

    Additional information

    Yan Chen and Xiangdong Chen contributed equally to this study.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Chen, Y., Chen, X., Yu, J. et al. JAB1 is Involved in Neuropathic Pain by Regulating JNK and NF-κB Activation After Chronic Constriction Injury. Neurochem Res 41, 1119–1129 (2016). https://doi.org/10.1007/s11064-015-1802-z

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11064-015-1802-z

    Keywords

    Search

    Navigation