Spinal release of tumour necrosis factor activates c-Jun N-terminal kinase and mediates inflammation-induced hypersensitivity

D. B. Bas, S. Abdelmoaty, K. Sándor, S. Codeluppi, B. Fitzsimmons, J. Steinauer, X. Y. Hua, T. L. Yaksh, Camilla I. Svensson

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Abstract: Background Mounting evidence points to individual contributions of tumour necrosis factor-alpha (TNF) and the c-Jun N-terminal kinase (JNK) pathway to the induction and maintenance of various pain states. Here we explore the role of spinal TNF and JNK in carrageenan-induced hypersensitivity. As links between TNF and JNK have been demonstrated in vitro, we investigated if TNF regulates spinal JNK activity in vivo. Methods TNF levels in lumbar cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay, spinal TNF gene expression by real-time polymerase chain reaction and TNF protein expression, JNK and c-Jun phosphorylation by western blotting. The role of spinal TNF and JNK in inflammation-induced mechanical and thermal hypersensitivity was assessed by injecting the TNF inhibitor etanercept and the JNK inhibitors SP600125 and JIP-1 intrathecally (i.t.). TNF-mediated regulation of JNK activity was examined by assessing the effect of i.t. etanercept on inflammation-induced spinal JNK activity. Results TNF levels were increased in CSF and spinal cord following carrageenan-induced inflammation. While JNK phosphorylation followed the same temporal pattern as TNF, c-jun was only activated at later time points. Intrathecal injection of TNF and JNK inhibitors attenuated carrageenan-induced mechanical and thermal hypersensitivity. TNF stimulation induced JNK phosphorylation in cultured spinal astrocytes and blocking the spinal actions of TNFâ€...in vivo by i.t. injection of etanercept reduced inflammation-induced spinal JNK activity. Conclusions Here we show that spinal JNK activity is dependent on TNF and that both TNF and the JNK signalling pathways modulate pain-like behaviour induced by peripheral inflammation.

Original languageEnglish
Pages (from-to)260-270
Number of pages11
JournalEuropean Journal of Pain (United Kingdom)
Volume19
Issue number2
DOIs
Publication statusPublished - Feb 1 2015

Fingerprint

JNK Mitogen-Activated Protein Kinases
Hypersensitivity
Tumor Necrosis Factor-alpha
Inflammation
Phosphotransferases
Carrageenan
Phosphorylation
Cerebrospinal Fluid
Hot Temperature
Pain
Spinal Injections

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Spinal release of tumour necrosis factor activates c-Jun N-terminal kinase and mediates inflammation-induced hypersensitivity. / Bas, D. B.; Abdelmoaty, S.; Sándor, K.; Codeluppi, S.; Fitzsimmons, B.; Steinauer, J.; Hua, X. Y.; Yaksh, T. L.; Svensson, Camilla I.

In: European Journal of Pain (United Kingdom), Vol. 19, No. 2, 01.02.2015, p. 260-270.

Research output: Contribution to journalArticle

Bas, DB, Abdelmoaty, S, Sándor, K, Codeluppi, S, Fitzsimmons, B, Steinauer, J, Hua, XY, Yaksh, TL & Svensson, CI 2015, 'Spinal release of tumour necrosis factor activates c-Jun N-terminal kinase and mediates inflammation-induced hypersensitivity', European Journal of Pain (United Kingdom), vol. 19, no. 2, pp. 260-270. https://doi.org/10.1002/ejp.544
Bas, D. B. ; Abdelmoaty, S. ; Sándor, K. ; Codeluppi, S. ; Fitzsimmons, B. ; Steinauer, J. ; Hua, X. Y. ; Yaksh, T. L. ; Svensson, Camilla I. / Spinal release of tumour necrosis factor activates c-Jun N-terminal kinase and mediates inflammation-induced hypersensitivity. In: European Journal of Pain (United Kingdom). 2015 ; Vol. 19, No. 2. pp. 260-270.
@article{092b44f1683844c0a763991d90111ed4,
title = "Spinal release of tumour necrosis factor activates c-Jun N-terminal kinase and mediates inflammation-induced hypersensitivity",
abstract = "Abstract: Background Mounting evidence points to individual contributions of tumour necrosis factor-alpha (TNF) and the c-Jun N-terminal kinase (JNK) pathway to the induction and maintenance of various pain states. Here we explore the role of spinal TNF and JNK in carrageenan-induced hypersensitivity. As links between TNF and JNK have been demonstrated in vitro, we investigated if TNF regulates spinal JNK activity in vivo. Methods TNF levels in lumbar cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay, spinal TNF gene expression by real-time polymerase chain reaction and TNF protein expression, JNK and c-Jun phosphorylation by western blotting. The role of spinal TNF and JNK in inflammation-induced mechanical and thermal hypersensitivity was assessed by injecting the TNF inhibitor etanercept and the JNK inhibitors SP600125 and JIP-1 intrathecally (i.t.). TNF-mediated regulation of JNK activity was examined by assessing the effect of i.t. etanercept on inflammation-induced spinal JNK activity. Results TNF levels were increased in CSF and spinal cord following carrageenan-induced inflammation. While JNK phosphorylation followed the same temporal pattern as TNF, c-jun was only activated at later time points. Intrathecal injection of TNF and JNK inhibitors attenuated carrageenan-induced mechanical and thermal hypersensitivity. TNF stimulation induced JNK phosphorylation in cultured spinal astrocytes and blocking the spinal actions of TNF{\^a}€...in vivo by i.t. injection of etanercept reduced inflammation-induced spinal JNK activity. Conclusions Here we show that spinal JNK activity is dependent on TNF and that both TNF and the JNK signalling pathways modulate pain-like behaviour induced by peripheral inflammation.",
author = "Bas, {D. B.} and S. Abdelmoaty and K. S{\'a}ndor and S. Codeluppi and B. Fitzsimmons and J. Steinauer and Hua, {X. Y.} and Yaksh, {T. L.} and Svensson, {Camilla I.}",
year = "2015",
month = "2",
day = "1",
doi = "10.1002/ejp.544",
language = "English",
volume = "19",
pages = "260--270",
journal = "European Journal of Pain",
issn = "1090-3801",
publisher = "W.B. Saunders Ltd",
number = "2",

}

TY - JOUR

T1 - Spinal release of tumour necrosis factor activates c-Jun N-terminal kinase and mediates inflammation-induced hypersensitivity

AU - Bas, D. B.

AU - Abdelmoaty, S.

AU - Sándor, K.

AU - Codeluppi, S.

AU - Fitzsimmons, B.

AU - Steinauer, J.

AU - Hua, X. Y.

AU - Yaksh, T. L.

AU - Svensson, Camilla I.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - Abstract: Background Mounting evidence points to individual contributions of tumour necrosis factor-alpha (TNF) and the c-Jun N-terminal kinase (JNK) pathway to the induction and maintenance of various pain states. Here we explore the role of spinal TNF and JNK in carrageenan-induced hypersensitivity. As links between TNF and JNK have been demonstrated in vitro, we investigated if TNF regulates spinal JNK activity in vivo. Methods TNF levels in lumbar cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay, spinal TNF gene expression by real-time polymerase chain reaction and TNF protein expression, JNK and c-Jun phosphorylation by western blotting. The role of spinal TNF and JNK in inflammation-induced mechanical and thermal hypersensitivity was assessed by injecting the TNF inhibitor etanercept and the JNK inhibitors SP600125 and JIP-1 intrathecally (i.t.). TNF-mediated regulation of JNK activity was examined by assessing the effect of i.t. etanercept on inflammation-induced spinal JNK activity. Results TNF levels were increased in CSF and spinal cord following carrageenan-induced inflammation. While JNK phosphorylation followed the same temporal pattern as TNF, c-jun was only activated at later time points. Intrathecal injection of TNF and JNK inhibitors attenuated carrageenan-induced mechanical and thermal hypersensitivity. TNF stimulation induced JNK phosphorylation in cultured spinal astrocytes and blocking the spinal actions of TNFâ€...in vivo by i.t. injection of etanercept reduced inflammation-induced spinal JNK activity. Conclusions Here we show that spinal JNK activity is dependent on TNF and that both TNF and the JNK signalling pathways modulate pain-like behaviour induced by peripheral inflammation.

AB - Abstract: Background Mounting evidence points to individual contributions of tumour necrosis factor-alpha (TNF) and the c-Jun N-terminal kinase (JNK) pathway to the induction and maintenance of various pain states. Here we explore the role of spinal TNF and JNK in carrageenan-induced hypersensitivity. As links between TNF and JNK have been demonstrated in vitro, we investigated if TNF regulates spinal JNK activity in vivo. Methods TNF levels in lumbar cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay, spinal TNF gene expression by real-time polymerase chain reaction and TNF protein expression, JNK and c-Jun phosphorylation by western blotting. The role of spinal TNF and JNK in inflammation-induced mechanical and thermal hypersensitivity was assessed by injecting the TNF inhibitor etanercept and the JNK inhibitors SP600125 and JIP-1 intrathecally (i.t.). TNF-mediated regulation of JNK activity was examined by assessing the effect of i.t. etanercept on inflammation-induced spinal JNK activity. Results TNF levels were increased in CSF and spinal cord following carrageenan-induced inflammation. While JNK phosphorylation followed the same temporal pattern as TNF, c-jun was only activated at later time points. Intrathecal injection of TNF and JNK inhibitors attenuated carrageenan-induced mechanical and thermal hypersensitivity. TNF stimulation induced JNK phosphorylation in cultured spinal astrocytes and blocking the spinal actions of TNFâ€...in vivo by i.t. injection of etanercept reduced inflammation-induced spinal JNK activity. Conclusions Here we show that spinal JNK activity is dependent on TNF and that both TNF and the JNK signalling pathways modulate pain-like behaviour induced by peripheral inflammation.

UR - http://www.scopus.com/inward/record.url?scp=84924037765&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924037765&partnerID=8YFLogxK

U2 - 10.1002/ejp.544

DO - 10.1002/ejp.544

M3 - Article

C2 - 24942612

AN - SCOPUS:84924037765

VL - 19

SP - 260

EP - 270

JO - European Journal of Pain

JF - European Journal of Pain

SN - 1090-3801

IS - 2

ER -