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

The Journal of Immunology : Official Journal of the American Association of Immunologists
Roland LangP J Murray

Abstract

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.

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Citations

Jul 26, 2002·International Journal of Hematology·David R Greaves, Siamon Gordon
Oct 20, 2004·The Journal of Biological Chemistry·Sébastien GingrasPeter J Murray
Mar 9, 2005·The Journal of Experimental Medicine·Suzanne A MilesDavid M Mosser
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