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

T. Ishikawa, Hiroaki Kume, Masashi Kondo, Y. Ito, K. Yamaki, K. Shimokata

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)808-815
Number of pages8
JournalClinical and Experimental Allergy
Volume33
Issue number6
DOIs
Publication statusPublished - 01-06-2003

Fingerprint

Transforming Growth Factors
Adrenergic Receptors
Interferons
Smooth Muscle
Colforsin
Isoproterenol
Theophylline
Rolipram
Phosphodiesterase Inhibitors
Phosphoric Diester Hydrolases
Adenylyl Cyclases
Signal Transduction
Guinea Pigs
Fibrosis
Inflammation

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

@article{2da7f40d00a040e1870b0c43fba16c30,
title = "Inhibitory effects of interferon-γ on the heterologous desensitization of β-adrenoceptors by transforming growth factor-β1 in tracheal smooth muscle",
abstract = "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.",
author = "T. Ishikawa and Hiroaki Kume and Masashi Kondo and Y. Ito and K. Yamaki and K. Shimokata",
year = "2003",
month = "6",
day = "1",
doi = "10.1046/j.1365-2222.2003.01681.x",
language = "English",
volume = "33",
pages = "808--815",
journal = "Clinical and Experimental Allergy",
issn = "0954-7894",
publisher = "Wiley-Blackwell",
number = "6",

}

Inhibitory effects of interferon-γ on the heterologous desensitization of β-adrenoceptors by transforming growth factor-β1 in tracheal smooth muscle. / Ishikawa, T.; Kume, Hiroaki; Kondo, Masashi; Ito, Y.; Yamaki, K.; Shimokata, K.

In: Clinical and Experimental Allergy, Vol. 33, No. 6, 01.06.2003, p. 808-815.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibitory effects of interferon-γ on the heterologous desensitization of β-adrenoceptors by transforming growth factor-β1 in tracheal smooth muscle

AU - Ishikawa, T.

AU - Kume, Hiroaki

AU - Kondo, Masashi

AU - Ito, Y.

AU - Yamaki, K.

AU - Shimokata, K.

PY - 2003/6/1

Y1 - 2003/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0037533039&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037533039&partnerID=8YFLogxK

U2 - 10.1046/j.1365-2222.2003.01681.x

DO - 10.1046/j.1365-2222.2003.01681.x

M3 - Article

C2 - 12801317

AN - SCOPUS:0037533039

VL - 33

SP - 808

EP - 815

JO - Clinical and Experimental Allergy

JF - Clinical and Experimental Allergy

SN - 0954-7894

IS - 6

ER -