Am. J. Respir. Crit. Care Med., Volume 165, Number 7, April 2002, 996-1004

Nuclear Factor-B Activation in Alveolar Macrophages Requires IB kinase-, but Not Nuclear Factor-B Inducing Kinase

MATTHEW CONRON, EVANGELOS ANDREAKOS, PANAGIOTIS PANTELIDIS, CLIVE SMITH, HUW L. C. BEYNON, ROLAND M. DUBOIS, and BRIAN M. J. FOXWELL

Kennedy Institute of Rheumatology (KIR), Hammersmith, London; Interstitial Lung Disease Unit, Royal Brompton Hospital, London; and Department of Medicine, Royal Free Hospital, London, United Kingdom

Cytokine mediated activation of alveolar macrophages (AMs) is an important event in the pathogenesis of fibrosing alveolitis (FA). Through membrane-associated antigens, cytokines (e.g., tumor necrosis-factor- and interleukin-1) are believed to activate a common kinase cascade that initiates the cytoplasmic degradation of IB and nuclear translocation of "nuclear factor-B" (NF-B). In the nucleus, NF-B promotes the transcription of genes encoding chemokines and cytokines involved in chronic inflammation. Preventing cytokine-mediated NF-B activation is a potential strategy for attenuating the lung injury that occurs in FA. Previously, we have demonstrated that, unlike AMs from healthy volunteers, AMs from patients with inflammatory lung diseases express the coxsackie/adenovirus receptor and the v integrins required for adenovirus (Adv) infection. This property allows Adv-mediated transgene delivery to diseased, but not normal, AMs and analysis of molecular pathways involved in gene transcription. In this study, AMs were infected with Adv constructs expressing a defective  subunit of IB kinase (AdvIKKkd) and a defective NF-B inducing kinase (AdvNIKkd) to investigate the contribution of these molecules to NF-B activation. We observed that IKK, but not NIK, was required for NF-B activation. The results of this study identify IKK, but not NIK, as a potential therapeutic target in diseases that involve NF-B-dependent gene transcription.

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