Selected Contribution: TNF-α modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl

Abstract

Although the mechanisms that underlie airway hyperresponsiveness 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-α, 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-α 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-α, carbachol-induced isometric force was significantly increased by 30% compared with those treated with diluent alone ( P < 0.05). TNF-α also augmented KCl-induced force generation by 70% compared with rings treated with diluent alone ( P < 0.01). The enhancing effect of TNF-α on carbachol-induced isometric force generation was completely abrogated in the tracheal rings obtained from TNF-α receptor (TNFR)1-deficient mice and in control rings treated with a TNF-α mutant that solely activates TNFR2. TNF-α also attenuated relaxation responsiveness to isoproterenol but not to PGE2 or forskolin. TNF-α modulatory effects on GPCR-induced ASM responsiveness were completely abrogated by pertussis toxin, an inhibitor of Giα proteins. Taken together, these data suggest that TNF-α may participate in the development of airway hyperresponsiveness in asthma via the modulation of ASM responsiveness to both contractile and β-adrenoceptor GPCR agonists.