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Published ahead of print on July 31, 2003, doi:10.1164/rccm.200205-479OC

Am. J. Respir. Crit. Care Med., Volume 168, Number 10, November 2003, 1190-1198

A more recent version of this article appeared on November 15, 2003
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Submitted on May 28, 2002
Accepted on July 30, 2003

Persistent activation of NF-{kappa}B signalling pathway in severe uncontrolled asthma

Rosalia Gagliardo1*, Pascal Chanez2, Marc Mathieu2, Andreina Bruno1, Giorgia Costanzo1, Claire Gougat2, Isabelle Vachier2, Jean Bousquet2, Giovanni Bonsignore3, and Antonio M Vignola4

1 Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Palermo, Italy, 2 U454 and Service des Maladies Respiratoires, Institut National de la Sante et de la Recherche Medicale, Montpellier, France, 3 Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Palermo, Italy; Istituto di Medicina Generale e Pneumologia, Universita' degli Studi di Palermo, Palermo, Italy, 4 Istituto di Medicina Generale e Pneumologia, Universita' degli Studi di Palermo, Palermo, Italy; Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Palermo, Italy

* To whom correspondence should be addressed. E-mail: gagliardo.r{at}iol.it.

The transcription factor NF-kB is inactive when bound to its inhibitory protein IkBa. Upon cell stimulation with inflammatory signals, IkBa is phosphorylated by IkB kinases (IKK) and subsequently degraded. Freed NF-kB then induces expression of cytokines like GM-CSF, IL-8 and RANTES. These mediators are overexpressed in asthma and are down-regulated by glucocorticoids (GCs) through NF-kB activity repression. However, high levels of GM-CSF, IL-8 and RANTES are released by PBMC isolated from severe asthmatics despite continuous systemic GC treatment. We report that these mediators are markedly decreased by pyrrolidinedithiocarbamate, an inhibitor of NF-kB activation. To further characterize the persistent NF-kB activation in severe asthma, we analyzed expression of various components of this activation pathway in healthy subjects and in asthmatics with mild controlled, moderate and severe uncontrolled disease. We found high amount of phosphorylated-IkBa characterizing the three asthmatic groups. Western blot analyses indicated that in PBMC the IKKb and p65 levels were greater in moderate and severe asthmatics than in normals. EMSA and immunocytochemistry showed a greater activation status of p65 in severe asthmatics. Our data suggest that exaggerated NF-kB activation perpetuates inflammatory mediators production in severe asthma.
Key words: severe asthma, inflammation, glucocorticoids, nuclear factor-kappaB.




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