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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.

Type

Journal article

Journal

J Immunol

Publication Date

01/04/2002

Volume

168

Pages

3402 - 3411

Keywords

Animals, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Autocrine Communication, Cell Count, Cells, Cultured, Colony Count, Microbial, Epitopes, B-Lymphocyte, Epitopes, T-Lymphocyte, Female, Gene Dosage, Humans, Infertility, Male, Injections, Intraperitoneal, Interferon-gamma, Interleukin-10, Interleukin-12, Lipopolysaccharides, Lymphoid Tissue, Macrophage Activation, Macrophages, Male, Mice, Mice, Transgenic, Mycobacterium bovis, Myeloid Cells, Oligopeptides, Peptides, Promoter Regions, Genetic, Recombinant Fusion Proteins, Signal Transduction, Tuberculosis, Tumor Necrosis Factor-alpha