Inhibitory effects of interferon-gamma on the heterologous desensitization of beta-adrenoceptors by transforming growth factor-beta 1 in tracheal smooth muscle.
BACKGROUND
Transforming growth factor-beta1 (TGF-beta 1) is generally considered to play an important role in the pathogenesis of chronic inflammation and fibrosis.


OBJECTIVE
This study was designed to determine mechanisms of reduced responsiveness of guinea-pig tracheal smooth muscle to beta-adrenoceptor agonists by TGF-beta 1, 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-beta 1 for 4-8 h, the inhibitory effects of 1 microm isoprenaline (ISO) and 10 microm forskolin on 1 microm MCh-induced contraction were markedly reduced in a concentration-dependent fashion. The desensitization by TGF-beta 1 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-beta 1 were 0.039 +/- 0.02 and 0.38 +/- 0.28 microm, respectively. The values of EC50 for the curves for forskolin under these conditions were 0.50 +/- 0.12 and 0.89 +/- 0.21 microm, respectively. On the other hand, the inhibitory effects of phosphodiesterase inhibitors such as theophylline and rolipram were not attenuated after exposure to TGF-beta 1. Concentration-inhibition curve for ISO was shifted to the right after exposure to 2000 pm TGF-beta 1 for 8 h more than that curve for forskolin. In contrast, the curve for theophylline was not shifted to the right by TGF-beta 1. When the tissues were incubated with TGF-beta 1 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-beta 1 in a concentration-dependent fashion. After exposure to TGF-beta 1, 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.


CONCLUSIONS
Impairment of the beta-adrenoceptors/adenylyl cyclase pathway are involved in heterologous desensitization of beta-adrenoceptors induced by TGF-beta 1 in airway smooth muscle. IFN-gamma functionally suppresses this phenomenon via cAMP-independent processes. Phosphodiesterase is still intact under this condition.
Ishikawa
T
T
Division of Respiratory medicine, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Kume
H
H
Kondo
M
M
Ito
Y
Y
Yamaki
K
K
Shimokata
K
K
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D016210:Methacholine Chloride / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D014132:Trachea; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D016212:Transforming Growth Factor beta; D016210:Methacholine Chloride; D005576:Colforsin; D007371:Interferon-gamma; D000242:Cyclic AMP; D007545:Isoproterenol