Interleukin 12 and tumor necrosis factor α are costimulators of interferon γ production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist

C. S. Tripp, S. F. Wolf, E. R. Unanue

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743 Scopus citations

Abstract

Listeriosis in mice with the severe combined immunodeficiency (SCID) mutation is an established model in vivo and in vitro of interferon γ (IFN- γ)-dependent macrophage activation by natural killer (NK) cells during the development of natural immunity. We demonstrate that IFN-γ production from SCID splenocytes is stimulated by interleukin (IL) 12, tumor necrosis factor α (TNF-α), and IL-2 but is inhibited by IL-10. IL-10, IL-12, and TNF are induced by heat-killed Listeria monocytogenes (hk-LM) from SCID splenocytes and peritoneal macrophages. IL-12 production is necessary for hk-LM to stimulate IFN-γ production by SCID splenocytes since neutralization of IL- 12 totally blocks IFN-γ production in this system. TNF-α and IL-2 act synergistically with IL-12 to augment IFN-γ production. Also, exogenous IL- 2 increases the response of NK cells to hk-LM or to IL-12 and TNF-α. In contrast, IL-10 inhibits hk-LM-induced IFN-γ production at two levels: (i) by inhibiting TNF and IL-12 production from these cultures (presumably from the macrophage) and (ii) by inhibiting the stimulatory effects of IL-12 and TNF-α on NK-cell IFN-γ production. Thus, these data indicate that macrophage production of TNF-α and IL-12 stimulates the release of IFN-γ by NK cells and that IL-10 produced in response to hk-LM inhibits this response at the level of the macrophage and the NK cell.

Original languageEnglish
Pages (from-to)3725-3729
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number8
DOIs
StatePublished - 1993

Keywords

  • cytokines
  • macrophages
  • microbial infection
  • natural immunity

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