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Am. J. Respir. Cell Mol. Biol., Volume 25, Number 2, August, 2001 141-149

Alveolar Macrophages and T Cells from Sarcoid, but Not Normal Lung, Are Permissive to Adenovirus Infection and Allow Analysis of NF-kappa B–Dependent Signaling Pathways

Matthew Conron, Jan Bondeson, Panagiotis Pantelidis, Huw L. C. Beynon, Marc Feldmann, Roland M. duBois, and Brian M. J. Foxwell

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

Adenovirus (Adv)-mediated gene transfer requires efficient infection of target cells. The objective of this study was to establish whether alveolar macrophages (AM) and T cells (AT) from sarcoid patients were permissive to infection with Adv vectors and if this property could be used to investigate cytokine gene regulation. Sarcoid and normal bronchoalveolar lavage (BAL) specimens infected with Adv vectors expressing either beta -galactosidase or a green fluorescent protein were analyzed for transgene expression by fluorescence-activated cell sorter (FACS) and direct immunofluorescence, respectively. Expression of surface antigens previously associated with Adv infection, the coxsackie/adenovirus receptor (CAR), alpha vbeta 3, and alpha vbeta 5 integrins, was also assessed using FACS analysis. Sarcoid AM and AT were found to efficiently express Adv transgenes, unlike AM from normal volunteers, peripheral blood monocytes, and peripheral blood T cells. Cells permissive to Adv infection expressed the CAR and alpha vbeta 5 integrin (also alpha vbeta 3 integrin for AM). The data indicate that the upregulation of Adv receptors and the ability to infect sarcoid AM and AT are related to the inflammatory environment within the lung. Having demonstrated efficient Adv-mediated transgene delivery to sarcoid AM and AT, a construct encoding porcine Ikappa Balpha was then used to investigate the requirement for nuclear factor (NF)-kappa B in the regulation of cytokine gene expression in pulmonary sarcoidosis. Overexpression of Ikappa Balpha in sarcoid BAL specimens indicated that tumor necrosis factor-alpha and interleukin (IL)-6 production by AM and interferon (IFN)-gamma production by AT is NF-kappa B dependent, whereas IL-4 production by AT is NF-kappa B independent. This is the first occasion that the requirement for NF-kappa B in IFN-gamma gene expression within primary human T cells has been demonstrated. The results of this study have implications for the future investigation of molecular pathways in inflammatory lung disease.

Abbreviations: adenovirus vector, Adv; adenovirus vector encoding an Ikappa Balpha transgene, AdvIkappa Balpha ; adenovirus vector encoding beta -galactosidase, Advbeta gal; adenovirus vector encoding a green fluorescent protein, Adv-GFP; empty adenovirus vector, Adv0; alveolar macrophage(s), AM; alveolar T cell(s), AT; bronchoalveolar lavage, BAL; coxsackie/adenovirus receptor, CAR; enzyme-linked immunosorbent assay, ELISA; electrophoretic mobility shift assay, EMSA; fluorescence-activated cell sorter, FACS; green fluorescent protein, GFP; interferon, IFN; interleukin, IL; lipopolysaccharide, LPS; monoclonal antibody, mAb; macrophage colony-stimulating factor, M-CSF; multiplicity of infection, MOI; nuclear factor, NF; p42/44 mitogen-activated protein kinase, p42/44 MAPK; standard error of the mean, SEM; T helper, Th.




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