Antigen-induced alveolitis: cytokine production in a mouse model.
Mice of the C57BL/6 strain were injected intraperitoneally with 10(8) sheep red blood cells (SRBC), then instilled intratracheally with 10(8) SRBC two to three weeks later. After a single intratracheal exposure, a significant cellular infiltrate occurred, composed mostly of macrophages and lymphocytes. Lymphocytes proliferated significantly in response to SRBC antigen in vitro and released interleukin-2 (IL-2). Alveolar macrophages isolated from mice challenged with SRBC released higher levels of IL-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha) upon in vitro lipopolysaccharide (LPS) stimulation compared to unprimed, challenged mice or mice receiving intraperitoneal SRBC alone. Lymphocytes from primed mice challenged three times with SRBC proliferated significantly less in response to the antigen than mice receiving one SRBC challenge and released significant levels of interferon gamma (IFN-gamma). Bronchoalveolar macrophages isolated from primed mice given three SRBC challenges released slightly higher levels of TNF-alpha and IL-6 in response to LPS than those from unprimed mice. After the third instillation, levels of hydroxyproline in the lungs increased significantly, indicative of a fibrotic reaction. Neutralization of IL-1 (by anti-mouse type 1 IL-1 receptor) or TNF-alpha resulted in the partial abrogation of the initial neutrophil influx, with some effect on the subsequent lymphocyte and macrophage influx. Blocking IL-1 or IL-2 but not TNF-alpha also resulted in a significant decrease in lung hydroxyproline increase, as well as lung granulomatous response and fibrosis. Overall, these results suggest that lymphoproliferation in the lungs in response to an antigen can result in fibrosis, mediated in part by IL-2 and IL-1.
Denis
M
M
Department of Anatomy and Cell Biology, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.
Bisson
D
D
D000542:Alveolitis, Extrinsic Allergic / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism*; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D006099:Granuloma / Q000209:etiology; D006909:Hydroxyproline / Q000378:metabolism; D007114:Immunization; D007249:Inflammation; D007274:Injections, Intraperitoneal; D007322:Instillation, Drug; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008171:Lung Diseases / Q000209:etiology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000276:immunology / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000209:etiology; D012756:Sheep / Q000097:blood; D014132:Trachea; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000941:Antigens; D016207:Cytokines; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D006909:Hydroxyproline