Administration of interleukin-10 abolishes innate resistance to Listeria monocytogenes.
We have used severe-combined immunodeficient (SCID) mice to examine the immunoregulatory effects of interleukin (IL)-10 on innate resistance to infection with Listeria monocytogenes. Addition of heat killed Listeria to spleen cells from naive SCID mice resulted in secretion of interferon (IFN)-gamma from natural killer cells in vitro. This response was enhanced up to 15-fold in the presence of exogenous IL-2, but was completely ablated by addition of IL-10 with IC50 of less than 0.5 U/ml. Infection of SCID mice with viable Listeria in vivo resulted in a prolonged course of infection eventually causing death by 12-14 days, whereas daily administration of IL-10 increased bacterial replication in the liver and spleen by up to 1000-fold resulting in death by day 4 post-infection. The immunosuppressive actions of IL-10 in vivo were also observed in immunocompetent BALB/c mice, whereas doses as low as 100 U/day converted a sublethal infection to 100% mortality. To study the events controlling expression of endogenous IL-10, peritoneal macrophage monolayers were challenged with Listeria after preincubation with a panel of recombinant cytokines. IFN-gamma primed macrophages for enhanced tumor necrosis factor (TNF) secretion, but inhibited IL-10 production, whereas granulocyte/macrophage colony-stimulating factor (CSF), macrophage CSF and also IL-4 enhanced macrophage IL-10 responses after ingestion of Listeria in vitro. Finally, monoclonal antibody neutralization of IFN-gamma during infection of SCID mice with Listeria inhibited TNF-alpha mRNA, but augmented expression of IL-10 mRNA in infected tissues. These results demonstrate that exogenous Il-10 is a potent immunosuppressive cytokine in the context of infection with an intracellular bacterium and that expression of endogenous IL-10 versus TNF is differentially regulated by the cytokine environment of the macrophage.
Kelly
J P
JP
Department of Clinical Sciences, London School of Hygiene and Tropical Medicine, GB.
Bancroft
G J
GJ
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects / Q000494:pharmacology; D016753:Interleukin-10 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000494:pharmacology*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D013045:Species Specificity; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma