Autocrine deactivation of macrophages in transgenic mice constitutively overexpressing IL-10 under control of the human CD68 promoter.

Journal article

IL-10 plays an essential role in blocking cytokine production by activated macrophages. To analyze the consequences of enforced expression of IL-10 by macrophages on innate and adaptive immune responses, we generated transgenic mice (macIL-10tg mice) expressing an epitope-tagged IL-10 (Flag-IL-10) under control of the human CD68 promoter. Expression of Flag-IL-10 was constitutive and restricted to macrophages, as shown by sorting splenocyte cell populations and intracellular staining for IL-10. Transgenic macrophages displayed suppressed production of TNF-alpha and IL-12 upon stimulation with LPS. When macIL-10tg mice were challenged with LPS, serum levels of proinflammatory cytokines were attenuated compared with controls. Infection with Mycobacterium bovis bacille Calmette-Guérin resulted in approximately 10-fold-higher bacterial loads than in wild-type mice. Normal T and B cell responses were observed in macIL-10tg mice, suggesting that macrophage-specific overexpression of IL-10 predominantly acts in an autocrine/paracrine manner, resulting in chronically deactivated macrophages that manifest an impaired ability to control pathogens.

Authors: Lang, R; Rutschman, R; Greaves, D; Murray, P

• Publication status: Published
• Journal: Journal of Immunology
• Volume: 168
• Issue: 7
• Pages: 3402-3411
• Publication date: 2002-04-01
• DOI: 10.4049/jimmunol.168.7.3402
• EISSN: 1550-6606
• ISSN: 0022-1767
• Language: English
• Keywords: Antigens, CD; Lipopolysaccharides; Mice; Female; Animals; Autocrine Communication; Tuberculosis; Injections, Intraperitoneal; Interferon-gamma; Cell Count; Peptides; Lymphoid Tissue; Gene Dosage; Mycobacterium bovis; Promoter Regions, Genetic; Interleukin-10; Tumor Necrosis Factor-alpha; Recombinant Fusion Proteins; Macrophages; Interleukin-12; Macrophage Activation; Myeloid Cells; Epitopes, B-Lymphocyte; Epitopes, T-Lymphocyte; Antigens, Differentiation, Myelomonocytic; Male; Cells, Cultured; Signal Transduction; Colony Count, Microbial; Humans; Mice, Transgenic; Infertility, Male