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TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling.

Publication ,  Journal Article
Lu, Y; Jiang, B-C; Cao, D-L; Zhang, Z-J; Zhang, X; Ji, R-R; Gao, Y-J
Published in: Pain
December 2014

The proinflammatory cytokines tumor necrosis factor (TNF) α and interleukin (IL) 1β have been strongly implicated in the pathogenesis of neuropathic pain, but the intracellular signaling of these cytokines in glial cells is not fully understood. TNF receptor-associated factor 6 (TRAF6) plays a key role in signal transduction in the TNF receptor superfamily and the IL-1 receptor superfamily. In this study, we investigated the role of TRAF6 in neuropathic pain in mice after spinal nerve ligation (SNL). SNL induced persistent TRAF6 upregulation in the spinal cord. Interestingly, TRAF6 was mainly colocalized with the astrocytic marker glial fibrillary acidic protein on SNL day 10 and partially expressed in microglia on SNL day 3. In cultured astrocytes, TRAF6 was upregulated after exposure to TNF-α or IL-1β. TNF-α or IL-1β also increased CCL2 expression, which was suppressed by both siRNA and shRNA targeting TRAF6. TRAF6 siRNA treatment also inhibited the phosphorylation of c-Jun N-terminal kinase (JNK) in astrocytes induced by TNF-α or IL-1β. JNK inhibitor D-NKI-1 dose-dependently decreased IL-1β-induced CCL2 expression. Moreover, spinal injection of TRAF6 siRNA decreased intrathecal TNF-α- or IL-1β-induced allodynia and hyperalgesia. Spinal TRAF6 inhibition via TRAF6 siRNA, shRNA lentivirus, or antisense oligodeoxynucleotides partially reversed SNL-induced neuropathic pain and spinal CCL2 expression. Finally, intrathecal injection of TNF-α-activated astrocytes induced mechanical allodynia, which was attenuated by pretreatment of astrocytes with TRAF6 siRNA. Taken together, the results suggest that TRAF6, upregulated in spinal cord astrocytes in the late phase after nerve injury, maintains neuropathic pain by integrating TNF-α and IL-1β signaling and activating the JNK/CCL2 pathway in astrocytes.

Duke Scholars

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Published In

Pain

DOI

EISSN

1872-6623

Publication Date

December 2014

Volume

155

Issue

12

Start / End Page

2618 / 2629

Location

United States

Related Subject Headings

  • Up-Regulation
  • Tumor Necrosis Factor-alpha
  • TNF Receptor-Associated Factor 6
  • Spinal Cord
  • Signal Transduction
  • RNA, Messenger
  • Pain Measurement
  • Neuralgia
  • Mice, Inbred ICR
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lu, Y., Jiang, B.-C., Cao, D.-L., Zhang, Z.-J., Zhang, X., Ji, R.-R., & Gao, Y.-J. (2014). TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling. Pain, 155(12), 2618–2629. https://doi.org/10.1016/j.pain.2014.09.027
Lu, Ying, Bao-Chun Jiang, De-Li Cao, Zhi-Jun Zhang, Xin Zhang, Ru-Rong Ji, and Yong-Jing Gao. “TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling.Pain 155, no. 12 (December 2014): 2618–29. https://doi.org/10.1016/j.pain.2014.09.027.
Lu Y, Jiang B-C, Cao D-L, Zhang Z-J, Zhang X, Ji R-R, et al. TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling. Pain. 2014 Dec;155(12):2618–29.
Lu, Ying, et al. “TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling.Pain, vol. 155, no. 12, Dec. 2014, pp. 2618–29. Pubmed, doi:10.1016/j.pain.2014.09.027.
Lu Y, Jiang B-C, Cao D-L, Zhang Z-J, Zhang X, Ji R-R, Gao Y-J. TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling. Pain. 2014 Dec;155(12):2618–2629.

Published In

Pain

DOI

EISSN

1872-6623

Publication Date

December 2014

Volume

155

Issue

12

Start / End Page

2618 / 2629

Location

United States

Related Subject Headings

  • Up-Regulation
  • Tumor Necrosis Factor-alpha
  • TNF Receptor-Associated Factor 6
  • Spinal Cord
  • Signal Transduction
  • RNA, Messenger
  • Pain Measurement
  • Neuralgia
  • Mice, Inbred ICR
  • Mice