Administration of two macrophage-derived interferon-gamma-inducing factors (IL-12 and IL-15) induces a lethal systemic inflammatory response in mice that is dependent on natural killer cells but does not require interferon-gamma

Cell Immunol. Mar-Apr 2002;216(1-2):31-42. doi: 10.1016/s0008-8749(02)00501-4.


Activation of macrophages by microbes results in the rapid production of monokines (e.g., interleukin-12 (IL-12), IL-15, and IL-18), which induce production of interferon-gamma (IFN-gamma) by natural killer (NK) cells. We examined the effects of administering IL-15 in combination with IL-12 in a murine toxicity model to determine how these two cytokines might contribute to the inflammatory state that accompanies infectious processes. The daily, simultaneous administration of IL-15 (3 x 10(5)U) and IL-12 (1 microg) to normal mice resulted in shock and 100% mortality within 3-7 days, whereas minimal toxicity was observed following the administration of IL-15 or IL-12 alone. Mice treated with IL-15 plus IL-12 exhibited lesions of the gastrointestinal tract, elevated serum levels of acute phase reactants and pro-inflammatory cytokines, and NK cell apoptosis. Neutralization of IFN-gamma, TNF-alpha, and IL-1beta was not protective in cytokine-treated mice, however, toxicity and death could be completely abrogated by depletion of NK cells. Mice deficient in the STAT4 transcription factor also exhibited complete protection while mice deficient in IFN-gamma or its downstream mediator, STAT1, did not. These findings suggest that cytokine- stimulated NK cells are able to promote systemic inflammation via the induction of STAT4-responsive genes other than IFN-gamma or TNF-alpha.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute-Phase Proteins / analysis
  • Animals
  • Apoptosis
  • CD3 Complex*
  • Cytokines / blood
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Dose-Response Relationship, Drug
  • Female
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interleukin-12 / antagonists & inhibitors
  • Interleukin-12 / toxicity*
  • Interleukin-15 / antagonists & inhibitors
  • Interleukin-15 / toxicity*
  • Intestinal Mucosa / pathology
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / pathology
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Tumor Necrosis Factor / deficiency
  • Receptors, Tumor Necrosis Factor / genetics
  • STAT1 Transcription Factor
  • STAT4 Transcription Factor
  • Shock / blood
  • Shock / chemically induced
  • Shock / immunology*
  • Time Factors
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / physiology


  • Acute-Phase Proteins
  • CD3 Complex
  • CD3E protein, human
  • Cytokines
  • DNA-Binding Proteins
  • Interleukin-15
  • Receptors, Antigen, T-Cell
  • Receptors, Tumor Necrosis Factor
  • STAT1 Transcription Factor
  • STAT4 Transcription Factor
  • Stat1 protein, mouse
  • Stat4 protein, mouse
  • Trans-Activators
  • Interleukin-12
  • Interferon-gamma