Administration of interleukin-10 abolishes innate resistance to Listeria monocytogenes

Eur J Immunol. 1996 Feb;26(2):356-64. doi: 10.1002/eji.1830260214.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Female
  • Immunity, Innate / drug effects
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / drug effects
  • Interferon-gamma / pharmacology
  • Interleukin-10 / administration & dosage*
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / pharmacology*
  • Interleukin-2 / administration & dosage
  • Interleukin-2 / pharmacology
  • Listeriosis / immunology*
  • Listeriosis / metabolism
  • Macrophage Activation / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Species Specificity
  • Spleen / cytology
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Interleukin-2
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interferon-gamma