Tumour necrosis factor-alpha activates a calcium sensitization pathway in guinea-pig bronchial smooth muscle

J R M Parris, H J Cooban, A F Littlejohn, D J MacEwan, G F Nixon

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Abstract

1. The effects of tumour necrosis factor-alpha (TNF) on guinea-pig bronchial smooth muscle contractility were investigated.

2. The Ca2+-activated contractile response of permeabilized bronchial smooth muscle strips was significantly increased after incubation with 1 mu g ml(-1) TNF for 45 min. This TNF-induced effect was not due to a further increase in intracellular Ca2+.

3. The TNF-induced Ca2+ sensitization was, at least partly, the result of an increase in myosin light chain(20) phosphorylation.

4. The intracellular signalling pathway involved in this effect of TNF was further investigated. Sphingomyelinase, a potential mediator of TNF, had no effect on Ca2+ sensitivity of permeabilized bronchial smooth muscle. Also, p42/p44 mitogen-activated protein kinase (p42/p44(mapk)), activated by TNF in some cell types, did not show an increased activation in bronchial smooth muscle after TNF treatment.

5. In conclusion, TNF may activate a novel signalling pathway in guinea-pig bronchial smooth muscle leading to an increase in myosin light chain(20) phosphorylation and a subsequent increase in Ca2+ sensitivity of the myofilaments. This pathway does not appear to involve sphingomyelinase-liberated ceramides or activation of p42/p44(mapk). Given the importance of TNF in asthma, this TNF-induced Ca2+ sensitization of the myofilaments may represent a mechanism responsible for airway hyper-responsiveness.

Original languageEnglish
Pages (from-to)561-569
Number of pages9
JournalThe Journal of Physiology
Volume518
Publication statusPublished - 1999

Keywords

  • RHO-ASSOCIATED KINASE
  • MEDIATED CA2+ SENSITIZATION
  • LIGHT-CHAIN PHOSPHORYLATION
  • PHOSPHOLIPASE A(2)
  • PROTEIN
  • RECEPTOR
  • CELLS
  • PHOSPHATASE
  • RELEASE
  • CONTRACTIONS

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