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modulates Murine Tracheal Rings responsiveness to G-protein coupled receptor agonists and KCL
1 Department of Medicine, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: amrani{at}mail.med.upenn.edu.
Although the mechanisms that underlie airway hyper-responsiveness (AHR) in asthma are complex and involve a variety of factors, evidence now suggests that intrinsic abnormalities in airway smooth muscle (ASM) may play an important role. We previously reported that TNF
, a cytokine involved in asthma, augments G-protein coupled receptor (GPCR) agonist-evoked calcium responses in cultured ASM cells. Here we have extended our previous studies by investigating whether TNF also modulates the contractile and relaxant responses to GPCR activation using cultured murine tracheal rings. We found that in tracheal rings treated with 50 ng/ml TNF, carbachol-induced isometric force was significantly increased by 30% as compared with those treated with diluent alone (p < 0.05). TNF also augmented KCl-induced force generation by 70% as compared with those treated with diluent alone (p < 0.01). The enhancing effect of TNF on carbachol-induced isometric force generation was completely abrogated in the tracheal rings obtained from TNFR1-deficient mice and in control rings treated with a TNF mutant that solely activates TNFR2. TNFa also attenuated relaxation responsiveness to isoproterenol but not to PGE2 or forskolin. TNF modulatory effects on GPCR-induced ASM responsiveness were completely abrogated by pertussis toxin, an inhibitor of Gai proteins. Taken together, these data suggest that TNF may participate in the development of AHR in asthma via the modulation of ASM responsiveness to both contractile and 
-adrenoceptor GPCR agonists.
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