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Asthma pp 187-197 | Cite as

Can cytokines in asthma be modulated by theophylline?

  • A. M. Vignola
  • M. Spatafora
  • G. Chiappara
  • A. M. Merendino
  • E. Pace
  • D. D’Amico
  • V. Bellia
  • G. Bonsignore

Summary

Theophylline (1,3 dimethylxanthine) is one of the most widely used drugs in the therapy of bronchial asthma and chronic obstructive pulmonary diseases. It is now being increasingly recognized that theophylline is able to down-regulate, both in-vitro and in-vivo, a variety of inflammatory and immune cell functions, such as the late-phase reaction after challenge with the occupational agent toluene diisocyanate and the bronchial responsiveness. The suppressive activity of theophylline is due to its ability to decrease the release of inflammatory mediators and might have important implications with regards to its therapeutic activity in asthma. In this report we summarize the effects of theophylline on TNF-α release, an inflammatory mediator which plays a key role in the pathogenesis of airways inflammation associated with bronchial asthma, by human peripheral blood monocytes (BM) and alveolar macrophages (AM) as well as on the activation and the proliferation of lymphocytes.

The data reported in this paper show that theophylline suppresses TNF-α release and TNF-α gene expression by BM and AM in a dose- dependent fashion at a concentration comparable to the in-vivo therapeutic levels of theophylline in the blood with a maximal inhibition at 2 h and that removal of theophylline after pre-incubation completely abrogates the inhibitory activity on TNF-α release, demonstrating that the continuous presence of the drug is required for suppression of TNF-α release.

In addition, theophylline is also able to affect the function of lymphocytes reducing their activation and proliferation by decreasing the production of IL-2, IL-2 receptor, transferrin and class IMHC antigens.

These data indicate that theophylline is capable of modulating important inflammatory and immune processes and that the therapeutic activity of this drug might be partly related to its down-regulating effects.

Keywords

Alveolar Macrophage Mononuclear Phagocyte Human Peripheral Blood Monocyte Late Asthmatic Reaction Diaphragmatic Contractility 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Zusammenfassung

Können Cytokine beim Asthma durch Theophyllin moduliert werden? Asthma ist eine chronisch-entzündliche Erkrankung, welche durch die Anhäufung von entzündlichen und immunologischen Effektorzellen (wie Eosinophile, Lymphozyten, Mastzellen und Makrophagen) in den Atemwegen und in der Bronchialschleimhaut charakterisiert ist.

Diese Zellen spielen eine wichtige Rolle bei der Pathogenese der Erkrankung, in dem sie sich gegenseitig beeinflussen, aber auch auf die strukturellen Zellverbände durch Expression von Adhäsionsmolekülen und die Freisetzung von Entzündungscytokinen wirken.

Wir haben angenommen, daß unter diesen Cytokinen der Tumornekrosisfaktor Alpha (TNF Alpha), ein 17-dK Cytokin, das von Lipopolysaccharid (LPS)-stimulierten mononukleären Phagozyten produziert wird, an wichtiger Stelle in die Pathogenese der Erkrankung involviert ist, weil es mit pleomorphen biologischen Aktivitäten ausgestattet ist.

Wir konnten sehen, daß Alveolarmakrophagen (AM) von schweren asthmatischen Patienten spontan große Mengen von TNF Alpha freisetzten (18 ± 3 ng/ml). Weiters sahen wir, daß Endothelin-1 die TNF- Alpha-Freisetzung bei normalen AM steigerte (4 ± 1 ng/ml), bei den AM von schweren Asthmatikern aber die TNF Alpha-Freisetzung aus den AM deutlich verminderte (14 ± 3 ng/ml). Diese Befunde legen nahe, daß beim Bronchialasthma die AM spontan dazu aktiviert werden, TNF Alpha freizusetzen, und daß ihre Fähigkeit vermindert wird, auf heterogene Reize zu reagieren.

Wir haben dann den Effekt von Theophyllin (1,3 Dimethylxanthine) auf die Freisetzung von TNF Alpha aus peripheren Blutmonozyten (BM) und AM untersucht. Diesbezügliche frühere Studien hatten folgendes ergeben:
  1. 1.

    Theophyllin vermindert die Funktion von Entzündungs- und Immunzellen durch Steigerung der intrazellulären Anhäufung von cAMP;

     
  2. 2.

    Die Freisetzung von TNF Alpha aus mononuklearen Phagozyten wird durch den cAMP Spiegel reguliert.

     

Theophyllin reduziert dosis-abhängig den bioaktiven TNF-Alpha- Ausstoß aus menschlichen BM. Eine signifikante Hemmung wurde bei 100 µM beobachtet (40,8 ± 5,9% bei Kontrollen; p < 0,01) und bei 50 µM (59,2 ± 4,8% bei Kontrollen; p < 0,05), während die Aktivität von Theophyllin bei 10 µM (71,2 ± 8,9% bei Kontrollen) nicht statistisch signifikant war. Die Aktivität erreichte ihr Maximum nach 2 Stunden und fiel nach 4 Stunden (59,0 ± 5,2% der Kontrollen) und nach 24 Stunden (89,1 ±3,1% der Kontrollen) wieder ab. Eine Northern Blot- Analyse von RNA, die aus menschlichen BM extrahiert worden waren, zeigte, daß Theophyllin imstande war, die TNF Alpha-Gen-Expression zu vermindern. Zumal TNF Alpha an wichtiger Stelle in der Pathogenese der bronchialen Hyperreaktivität und des Asthma involviert ist, lassen diese Befunde vermuten, daß die therapeutische Aktivität von Theophyllin zumindest teilweise über seinen Effekt auf den TNF Alpha Ausstoß von mononukleären Phagozyten erklärbar ist.

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Copyright information

© Springer-Verlag/Wien 1995

Authors and Affiliations

  • A. M. Vignola
    • 1
  • M. Spatafora
    • 2
  • G. Chiappara
    • 1
  • A. M. Merendino
    • 2
  • E. Pace
    • 1
  • D. D’Amico
    • 1
  • V. Bellia
    • 2
  • G. Bonsignore
    • 1
    • 2
  1. 1.Istituto di Fisiopatologia RespiratoriaC. N. R.PalermoItaly
  2. 2.Istituto di Medicina Generale e PneumologiaUniversità degli StudiPalermoItaly

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