Inhibitory effects of interferon-γ on the heterologous desensitization of β-adrenoceptors by transforming growth factor-β1 in tracheal smooth muscle
Article first published online: 10 JUN 2003
Clinical & Experimental Allergy
Volume 33, Issue 6, pages 808–815, June 2003
How to Cite
Ishikawa, T., Kume, H., Kondo, M., Ito, Y., Yamaki, K. and Shimokata, K. (2003), Inhibitory effects of interferon-γ on the heterologous desensitization of β-adrenoceptors by transforming growth factor-β1 in tracheal smooth muscle. Clinical & Experimental Allergy, 33: 808–815. doi: 10.1046/j.1365-2222.2003.01681.x
- Issue published online: 10 JUN 2003
- Article first published online: 10 JUN 2003
- Submitted 23 August 2002; revised 11 February 2003; accepted 28 February 2003
- airway 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 in airway smooth muscle. IFN-γ functionally suppresses this phenomenon via cAMP-independent processes. Phosphodiesterase is still intact under this condition.