Tumour necrosis factor-alpha activates a calcium sensitization pathway in guinea-pig bronchial smooth muscle.
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 microgram 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 chain20 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/p44mapk), 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 chain20 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/p44mapk. Given the importance of TNF in asthma, this TNF-induced Ca2+ sensitization of the myofilaments may represent a mechanism responsible for airway hyper-responsiveness.
Parris
J R
JR
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Cobban
H J
HJ
Littlejohn
A F
AF
MacEwan
D J
DJ
Nixon
G F
GF
D000818:Animals; D001980:Bronchi / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D018994:Myosin Light Chains / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D018994:Myosin Light Chains; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019950:Mitogen-Activated Protein Kinase 1; D013108:Sphingomyelin Phosphodiesterase; D002118:Calcium