Inhibitory effects of interferon-γ on the heterologous desensitization of β-adrenoceptors by transforming growth factor-β1 in tracheal smooth muscle

Background Transforming growth factor-beta1 (TGF-beta1) is generally considered to play an important role in the pathogenesis of chronic inflammation and fibrosis. Objective and methods This study was designed to determine mechanisms of reduced responsiveness of guinea-pig tracheal smooth muscle to beta-adrenoceptor agonists by TGF-beta1, using isometric tension records and tissue cAMP measurement. Moreover, we examined the involvement of the signal transduction processes of TGF-beta superfamily in the desensitization of beta-adrenoceptors. Results After exposure to 0.2-2000 pm TGF-beta1 for 4-8 h, the inhibitory effects of 1 muM isoprenaline (ISO) and 10 muM forskolin on 1 muM MCh-induced contraction were markedly reduced in a concentration-dependent fashion. The desensitization by TGF-beta1 was greater against ISO than for forskolin. The values of EC75 for the curves for ISO after exposure to the normal bathing solution and TGF-beta1 were 0.039 +/- 0.02 and 0.38 +/- 0.28 muM, respectively. The values of EC50 for the curves for forskolin under these conditions were 0.50 +/- 0.12 and 0.89 +/- 0.21 muM, respectively. On the other hand, the inhibitory effects of phosphodiesterase inhibitors such as theophylline and rolipram were not attenuated after exposure to TGF-beta1. Concentration-inhibition curve for ISO was shifted to the right after exposure to 2000 pM TGF-beta1 for 8 h more than that curve for forskolin. In contrast, the curve for theophylline was not shifted to the right by TGF-beta1. When the tissues were incubated with TGF-beta1 in the presence of IFN-gamma, an intracellular antagonist of TGF-beta signalling, IFN-gamma inhibited the reduced response to ISO and forskolin after exposure to TGF-beta1 in a concentration-dependent fashion. After exposure to TGF-beta1, the effects of cAMP accumulation of ISO was significantly reduced, however, neither forskolin-nor theophylline-induced cAMP accumulation was affected. IFN-gamma had no significant effect on cAMP accumulation either to ISO or forskolin. Conclusion Impairment of the beta-adrenoceptors/adenylyl cyclase pathway are involved in heterologous desensitization of beta-adrenoceptors induced by TGF-beta1 in airway smooth muscle. IFN-gamma functionally suppresses this phenomenon via cAMP-independent processes. Phosphodiesterase is still intact under this condition.