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Persistent Activation of Nuclear Factor–B Signaling Pathway in Severe Uncontrolled Asthma

Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche; Istituto di Medicina Generale e Pneumologia, Universita' degli Studi di Palermo, Palermo, Italy; and U454 and Service des Maladies Respiratoires, Institut National de la Santé et de la Recherche Médicale, CHU de Montpellier, Montpellier, France

Correspondence and requests for reprints should be addressed to Rosalia Gagliardo, Ph.D., Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Palermo, Via Ugo La Malfa 153, 90146 Palermo, Italy. E-mail: gagliardo.r{at}iol.it

The transcription factor nuclear factor–B (NF-B) is inactive when bound to its inhibitory protein IB. On cell stimulation with inflammatory signals, IB is phosphorylated by IB kinases and subsequently degraded. Freed NF-B then induces expression of cytokines such as granulocyte–macrophage colony-stimulating factor, interleukin-8, and regulated upon activation, normal T cell expressed and secreted. These mediators are overexpressed in asthma and are downregulated by glucocorticoids through NF-B activity repression. However, high levels of granulocyte–macrophage colony-stimulating factor, interleukin-8, and regulated upon activation, normal T cell expressed and presumably secreted are released by peripheral blood mononuclear cells isolated from patients with severe asthma despite continuous systemic glucocorticoid treatment. We report that these mediators are markedly decreased by pyrrolidinedithiocarbamate, an inhibitor of NF-B activation. To further characterize the persistent NF-B activation in severe asthma, we analyzed the expression of various components of this activation pathway in healthy subjects and in asthmatics with mild controlled, and moderate and severe uncontrolled disease. We found high amounts of phosphorylated IB characterizing the three asthmatic groups. Western blot analyses indicated that in peripheral blood mononuclear cells the IB kinase ß and p65 levels were greater in moderate and severe asthmatics than in normal subjects. Electrophoretic mobility shift assay and immunocytochemistry showed a greater activation status of p65 in severe asthmatics. Our data suggest that exaggerated NF-B activation perpetuates inflammatory mediators production in severe asthma.

Key Words: severe asthma • inflammation • glucocorticoids • nuclear factor–B

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