TNF-a receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones

J. Pollock, Shona Moira McFarlane, Michelle Connell, U. Zehavi, P. Vandenabeele, David Joseph MacEwan, Roderick Hamilton Scott

Research output: Contribution to journalArticle

142 Citations (Scopus)

Abstract

The cytokine tumour necrosis factor-alpha. (TNF) has been implicated in autoimmune diseases and may play an indirect role in activation of pain pathways. In this study we have investigated the possibility that TNF directly activates cultured neonatal rat dorsal root ganglion (DRG) neurones and provides a signalling pathway from cells in the immune system such as macrophages to sensory neurones. Expression of TNF receptor subtypes (TNFR1 and TNFR2) on sensory neurones was identified using immunohistochemistry, fluorescence-activated cell sorting analysis and RT-PCR. Biochemical and immunocytochemical analysis showed that TNF activated p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) but not p42/p44 MAPK. TNF treatment evoked transient Ca2+-dependent inward currents in 70% of DRG neurones. These TNF-evoked currents were significantly attenuated by ryanodine or thapsigargin or by inclusion of BAPTA in the patch pipette solution. Responses were also evoked in subpopulations of cultured DRG neurones by human mutant TNFs that cross-reacted with rat receptors and selectively activated TNFR1 or TNFR2 subtypes. TNF-evoked transient increases in [Ca2+](i) were also detected in 34% of fura-2-loaded DRG neurones. The link between TNF receptor activation and Ca2+ release from stores remains to be elucidated. However, responses to TNF were mimicked by sphingolipids, including sphingosine-1-phosphate, which evoked a transient rises in [Ca2+](i) in a pertussis toxin-insensitive manner in fura-2-loaded DRG neurones. We conclude that distinct receptors TNFR1 and TNFR2 are expressed on cultured DRG neurones and that they are functionally linked to intracellular Ca2+ mobilisation, a response that may involve sphingolipid signalling. (C) 2002 Elsevier Science Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)93-106
Number of pages13
JournalNeuropharmacology
Volume42
Issue number1
DOIs
Publication statusPublished - Jan 2002

Keywords

  • tumour necrosis factor
  • pain
  • sensory neurones
  • ryanodine
  • thapsigargin
  • Ca2+-activated current
  • intracellular Ca2+ stores
  • sphingolipids
  • sphingosine-1-phosphate
  • Ca2+ signalling
  • TUMOR-NECROSIS-FACTOR
  • CYCLIC ADP-RIBOSE
  • ROOT GANGLION NEURONS
  • SMOOTH-MUSCLE CELLS
  • SPHINGOSINE 1-PHOSPHATE
  • RHEUMATOID-ARTHRITIS
  • SIGNAL-TRANSDUCTION
  • INTRACELLULAR CALCIUM
  • SYMPATHETIC NEURONS
  • MAMMALIAN-CELLS

Cite this

Pollock, J., McFarlane, S. M., Connell, M., Zehavi, U., Vandenabeele, P., MacEwan, D. J., & Scott, R. H. (2002). TNF-a receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones. Neuropharmacology, 42(1), 93-106. https://doi.org/10.1016/S0028-3908(01)00163-0

TNF-a receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones. / Pollock, J.; McFarlane, Shona Moira; Connell, Michelle; Zehavi, U.; Vandenabeele, P.; MacEwan, David Joseph; Scott, Roderick Hamilton.

In: Neuropharmacology, Vol. 42, No. 1, 01.2002, p. 93-106.

Research output: Contribution to journalArticle

Pollock, J, McFarlane, SM, Connell, M, Zehavi, U, Vandenabeele, P, MacEwan, DJ & Scott, RH 2002, 'TNF-a receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones', Neuropharmacology, vol. 42, no. 1, pp. 93-106. https://doi.org/10.1016/S0028-3908(01)00163-0
Pollock, J. ; McFarlane, Shona Moira ; Connell, Michelle ; Zehavi, U. ; Vandenabeele, P. ; MacEwan, David Joseph ; Scott, Roderick Hamilton. / TNF-a receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones. In: Neuropharmacology. 2002 ; Vol. 42, No. 1. pp. 93-106.
@article{c42db6db1ab643b88efb77c401f1e43e,
title = "TNF-a receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones",
abstract = "The cytokine tumour necrosis factor-alpha. (TNF) has been implicated in autoimmune diseases and may play an indirect role in activation of pain pathways. In this study we have investigated the possibility that TNF directly activates cultured neonatal rat dorsal root ganglion (DRG) neurones and provides a signalling pathway from cells in the immune system such as macrophages to sensory neurones. Expression of TNF receptor subtypes (TNFR1 and TNFR2) on sensory neurones was identified using immunohistochemistry, fluorescence-activated cell sorting analysis and RT-PCR. Biochemical and immunocytochemical analysis showed that TNF activated p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) but not p42/p44 MAPK. TNF treatment evoked transient Ca2+-dependent inward currents in 70{\%} of DRG neurones. These TNF-evoked currents were significantly attenuated by ryanodine or thapsigargin or by inclusion of BAPTA in the patch pipette solution. Responses were also evoked in subpopulations of cultured DRG neurones by human mutant TNFs that cross-reacted with rat receptors and selectively activated TNFR1 or TNFR2 subtypes. TNF-evoked transient increases in [Ca2+](i) were also detected in 34{\%} of fura-2-loaded DRG neurones. The link between TNF receptor activation and Ca2+ release from stores remains to be elucidated. However, responses to TNF were mimicked by sphingolipids, including sphingosine-1-phosphate, which evoked a transient rises in [Ca2+](i) in a pertussis toxin-insensitive manner in fura-2-loaded DRG neurones. We conclude that distinct receptors TNFR1 and TNFR2 are expressed on cultured DRG neurones and that they are functionally linked to intracellular Ca2+ mobilisation, a response that may involve sphingolipid signalling. (C) 2002 Elsevier Science Ltd. All rights reserved.",
keywords = "tumour necrosis factor, pain, sensory neurones, ryanodine, thapsigargin, Ca2+-activated current, intracellular Ca2+ stores, sphingolipids, sphingosine-1-phosphate, Ca2+ signalling, TUMOR-NECROSIS-FACTOR, CYCLIC ADP-RIBOSE, ROOT GANGLION NEURONS, SMOOTH-MUSCLE CELLS, SPHINGOSINE 1-PHOSPHATE, RHEUMATOID-ARTHRITIS, SIGNAL-TRANSDUCTION, INTRACELLULAR CALCIUM, SYMPATHETIC NEURONS, MAMMALIAN-CELLS",
author = "J. Pollock and McFarlane, {Shona Moira} and Michelle Connell and U. Zehavi and P. Vandenabeele and MacEwan, {David Joseph} and Scott, {Roderick Hamilton}",
year = "2002",
month = "1",
doi = "10.1016/S0028-3908(01)00163-0",
language = "English",
volume = "42",
pages = "93--106",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "PERGAMON-ELSEVIER SCIENCE LTD",
number = "1",

}

TY - JOUR

T1 - TNF-a receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones

AU - Pollock, J.

AU - McFarlane, Shona Moira

AU - Connell, Michelle

AU - Zehavi, U.

AU - Vandenabeele, P.

AU - MacEwan, David Joseph

AU - Scott, Roderick Hamilton

PY - 2002/1

Y1 - 2002/1

N2 - The cytokine tumour necrosis factor-alpha. (TNF) has been implicated in autoimmune diseases and may play an indirect role in activation of pain pathways. In this study we have investigated the possibility that TNF directly activates cultured neonatal rat dorsal root ganglion (DRG) neurones and provides a signalling pathway from cells in the immune system such as macrophages to sensory neurones. Expression of TNF receptor subtypes (TNFR1 and TNFR2) on sensory neurones was identified using immunohistochemistry, fluorescence-activated cell sorting analysis and RT-PCR. Biochemical and immunocytochemical analysis showed that TNF activated p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) but not p42/p44 MAPK. TNF treatment evoked transient Ca2+-dependent inward currents in 70% of DRG neurones. These TNF-evoked currents were significantly attenuated by ryanodine or thapsigargin or by inclusion of BAPTA in the patch pipette solution. Responses were also evoked in subpopulations of cultured DRG neurones by human mutant TNFs that cross-reacted with rat receptors and selectively activated TNFR1 or TNFR2 subtypes. TNF-evoked transient increases in [Ca2+](i) were also detected in 34% of fura-2-loaded DRG neurones. The link between TNF receptor activation and Ca2+ release from stores remains to be elucidated. However, responses to TNF were mimicked by sphingolipids, including sphingosine-1-phosphate, which evoked a transient rises in [Ca2+](i) in a pertussis toxin-insensitive manner in fura-2-loaded DRG neurones. We conclude that distinct receptors TNFR1 and TNFR2 are expressed on cultured DRG neurones and that they are functionally linked to intracellular Ca2+ mobilisation, a response that may involve sphingolipid signalling. (C) 2002 Elsevier Science Ltd. All rights reserved.

AB - The cytokine tumour necrosis factor-alpha. (TNF) has been implicated in autoimmune diseases and may play an indirect role in activation of pain pathways. In this study we have investigated the possibility that TNF directly activates cultured neonatal rat dorsal root ganglion (DRG) neurones and provides a signalling pathway from cells in the immune system such as macrophages to sensory neurones. Expression of TNF receptor subtypes (TNFR1 and TNFR2) on sensory neurones was identified using immunohistochemistry, fluorescence-activated cell sorting analysis and RT-PCR. Biochemical and immunocytochemical analysis showed that TNF activated p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) but not p42/p44 MAPK. TNF treatment evoked transient Ca2+-dependent inward currents in 70% of DRG neurones. These TNF-evoked currents were significantly attenuated by ryanodine or thapsigargin or by inclusion of BAPTA in the patch pipette solution. Responses were also evoked in subpopulations of cultured DRG neurones by human mutant TNFs that cross-reacted with rat receptors and selectively activated TNFR1 or TNFR2 subtypes. TNF-evoked transient increases in [Ca2+](i) were also detected in 34% of fura-2-loaded DRG neurones. The link between TNF receptor activation and Ca2+ release from stores remains to be elucidated. However, responses to TNF were mimicked by sphingolipids, including sphingosine-1-phosphate, which evoked a transient rises in [Ca2+](i) in a pertussis toxin-insensitive manner in fura-2-loaded DRG neurones. We conclude that distinct receptors TNFR1 and TNFR2 are expressed on cultured DRG neurones and that they are functionally linked to intracellular Ca2+ mobilisation, a response that may involve sphingolipid signalling. (C) 2002 Elsevier Science Ltd. All rights reserved.

KW - tumour necrosis factor

KW - pain

KW - sensory neurones

KW - ryanodine

KW - thapsigargin

KW - Ca2+-activated current

KW - intracellular Ca2+ stores

KW - sphingolipids

KW - sphingosine-1-phosphate

KW - Ca2+ signalling

KW - TUMOR-NECROSIS-FACTOR

KW - CYCLIC ADP-RIBOSE

KW - ROOT GANGLION NEURONS

KW - SMOOTH-MUSCLE CELLS

KW - SPHINGOSINE 1-PHOSPHATE

KW - RHEUMATOID-ARTHRITIS

KW - SIGNAL-TRANSDUCTION

KW - INTRACELLULAR CALCIUM

KW - SYMPATHETIC NEURONS

KW - MAMMALIAN-CELLS

U2 - 10.1016/S0028-3908(01)00163-0

DO - 10.1016/S0028-3908(01)00163-0

M3 - Article

VL - 42

SP - 93

EP - 106

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

IS - 1

ER -