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.
|Number of pages||9|
|Journal||The Journal of Physiology|
|Publication status||Published - 1999|
- RHO-ASSOCIATED KINASE
- MEDIATED CA2+ SENSITIZATION
- LIGHT-CHAIN PHOSPHORYLATION
- PHOSPHOLIPASE A(2)