Autocrine deactivation of macrophages in transgenic mice constitutively overexpressing IL-10 under control of the human CD68 promoter.
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.
Lang
Roland
R
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Rutschman
Robert L
RL
Greaves
David R
DR
Murray
Peter J
PJ
D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics* / Q000502:physiology; D019898:Autocrine Communication / Q000276:immunology*; D002452:Cell Count; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007248:Infertility, Male / Q000235:genetics / Q000401:mortality; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics*; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008221:Lymphoid Tissue / Q000166:cytology; D008262:Macrophage Activation / Q000235:genetics*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009163:Mycobacterium bovis / Q000276:immunology; D022423:Myeloid Cells / Q000166:cytology; D009842:Oligopeptides; D010455:Peptides / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D007371:Interferon-gamma; D016753:Interleukin-10; D018664:Interleukin-12; D008070:Lipopolysaccharides; D009842:Oligopeptides; D010455:Peptides; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C085706:FLAG peptide