title: Functional IL-10 deficiency in the lung of cystic fibrosis (cftr(-/-)) and IL-10 knockout mice causes increased expression and function of B7 costimulatory molecules on alveolar macrophages.
abstract: Alveolar macrophages are poor APCs that only minimally express B7 costimulatory molecules. Because our previous data suggest that bronchial epithelial cells constitutively secrete IL-10, and IL-10 inhibits B7 expression in vitro, we hypothesized that this IL-10 is responsible for suppressing B7 expression on macrophages that enter the airways. Furthermore, because we have shown that cystic fibrosis (CF) lungs are deficient in IL-10, we hypothesized that bronchoalveolar macrophages (BALMs) from cystic fibrosis transmembrane conductance regulator (CFTR)(-/-) as well as IL-10(-/-) mice might express increased B7. Immunofluorescence for B7 was positive on BALMs from CF patients and CFTR(-/-) and IL-10(-/-) mice, but was negative on controls. FACS showed that 63.9% of BALMs from IL-10(-/-) mice were B7-1 positive, as were 67.4% of BALMs from CFTR(-/-) mice, whereas <7% of BALMs from wild-type controls were positive. Using BALMs to costimulate splenic T cells with anti-CD3 as a mitogen showed 9202 +/- 2107 cpm [(3)H]thymidine incorporation for BALMs from IL-10(-/-) mice and 4082 +/- 1036 cpm for BALMs from CFTR(-/-) mice, but <200 cpm with BALMs from either type of +/+ mouse. Treatment of CFTR(-/-) mice with recombinant mouse IL-10 reduced the B7 expression and costimulatory activity of the BALMs. These data suggest that the IL-10 secreted in the healthy lung may be responsible for the absence of B7 and poor costimulatory activity of BALMs and that reductions of pulmonary IL-10 in CF may enhance B7 expression and local immune responses.
authors.affiliation: Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Soltys
authors.forename: Tracey
authors.initials: T
authors.lastname: Bonfield
authors.forename: James
authors.initials: J
authors.lastname: Chmiel
authors.forename: Melvin
authors.initials: M
authors.lastname: Berger
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D051940:B7-2 Antigen; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008168:Lung / Q000276:immunology; D008213:Lymphocyte Activation; D016676:Macrophages, Alveolar / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D016753:Interleukin-10