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-β1 (TGF-β1) 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 β-adrenoceptor agonists by TGF-β1, using isometric tension records and tissue cAMP measurement. Moreover, we examined the involvement of the signal transduction processes of TGF-β superfamily in the desensitization of β-adrenoceptors. Results: After exposure to 0.2-2000 pM TGF-β1 for 4-8 h, the inhibitory effects of 1 μM isoprenaline (ISO) and 10 μM forskolin on 1 μM MCh-induced contraction were markedly reduced in a concentration-dependent fashion. The desensitization by TGF-β1 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-β1 were 0.039 ± 0.02 and 0.38 ± 0.28 μM, respectively. The values of EC₅₀ for the curves for forskolin under these conditions were 0.50 ± 0.12 and 0.89 ± 0.21 μM, respectively. On the other hand, the inhibitory effects of phosphodiesterase inhibitors such as theophylline and rolipram were not attenuated after exposure to TGF-β1. Concentration-inhibition curve for ISO was shifted to the right after exposure to 2000 pM TGF-β1 for 8 h more than that curve for forskolin. In contrast, the curve for theophylline was not shifted to the right by TGF-β1. When the tissues were incubated with TGF-β1 in the presence of IFN-γ, an intracellular antagonist of TGF-β signalling, IFN-γ inhibited the reduced response to ISO and forskolin after exposure to TGF-β1 in a concentration-dependent fashion. After exposure to TGF-β1, the effects of cAMP accumulation of ISO was significantly reduced, however, neither forskolin-nor theophylline-induced cAMP accumulation was affected. IFN-γ had no significant effect on cAMP accumulation either to ISO or forskolin. Conclusions: Impairment of the β-adrenoceptors/adenylyl cyclase pathway are involved in heterologous desensitization of β-adrenoceptors induced by TGF-β1 iin airway smooth muscle. IFN-γ functionally suppresses this phenomenon via cAMP-independent processes. Phosphodiesterase is still intact under this condition.