Adenovirus-mediated cytokine gene transfer at tissue sites. Overexpression of IL-6 induces lymphocytic hyperplasia in the lung.
The biologic function of cytokines may be best studied in the context of a defined tissue site. To establish a model for studying the function of IL-6 at local tissue sites, we targeted the IL-6 transgene into the bronchial epithelium in the lung of Sprague-Dawley rats by intratracheal administration of a recombinant human type 5 adenovirus with rat IL-6 cDNA incorporated into the E3 region of the viral genome. This approach led to a highly compartmentalized overexpression of the IL-6 transgene and production of bioactive protein within the lung for about 7 days post-infection. Associated with this overexpression of IL-6 was the development of profound local lymphocytic hyperplasia around day 7, characterized by the dramatic expansion of bronchial associated lymphoid aggregates and massive lymphocytic infiltration in the pulmonary parenchyma. Concurrently, there were strikingly increased numbers of lymphocytes in bronchoalveolar lavage fluids. The majority of these lymphocytes were found to be CD3+CD8+ cytotoxic T and CD3+CD4+ helper T cells with the remaining being primarily a small number of CD45R+ B cells. In addition, there was moderate bronchial and alveolar epithelial hyperplasia associated with lymphocytic hyperplasia. However, all of these changes subsided concomitant with the decrease in IL-6 expression and the lung seemed normal at 12 to 14 days post-infection. Thus, our study provides a tissue-specific transient transgene model for investigating cytokine functions in vivo and demonstrates that IL-6 has a profound stimulatory effect on the local lymphoid tissue in the lung.
Xing
Z
Z
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Braciak
T
T
Jordana
M
M
Croitoru
K
K
Graham
F L
FL
Gauldie
J
J
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D015152:Blotting, Northern; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004586:Electrophoresis / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics*; D006965:Hyperplasia / Q000276:immunology; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000473:pathology*; D016131:Lymphocyte Subsets / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection / Q000235:genetics; D001616:beta-Galactosidase / Q000096:biosynthesis
D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D001616:beta-Galactosidase