A fatal cytokine-induced systemic inflammatory response reveals a critical role for NK cells

William E. Carson, Haixin Yu, Julie Dierksheide, Klaus Pfeffer, Page Bouchard, Reed Clark, Joan Durbin, Albert S. Baldwin, Jacques Peschon, Philip R. Johnson, George Ku, Heinz Baumann, Michael A. Caligiuri

Research output: Contribution to journalArticlepeer-review

93 Scopus citations


The mechanism of cytokine-induced shock remains poorly understood. The combination of IL-2 and IL-12 has synergistic antitumor activity in vivo, yet has been associated with significant toxicity. We examined the effects of IL- 2 plus IL-12 in a murine model and found that the daily, simultaneous administration of IL-2 and IL-12 resulted in shock and 100% mortality within 4 to 12 days depending on the strain employed. Mice treated with IL-2 plus IL-12 exhibited NK cell apoptosis, pulmonary edema, degenerative lesions of the gastrointestinal tract, and elevated serum levels of proinflammatory cytokines and acute phase reactants. The actions of TNF-α, IFN-γ, macrophage-inflammatory protein-1α, IL-1, IL-1-converting enzyme, Fas, perforin, inducible nitric oxide synthase, and STAT1 did not contribute to the observed toxicity, nor did B or T cells. However, toxicity and death from treatment with IL-2 plus IL-12 could be completely abrogated by elimination of NK cells. These results suggest that the fatal systemic inflammatory response induced by this cytokine treatment is critically dependent upon NK cells, but does not appear to be mediated by the known effector molecules of this cellular compartment. These data may provide insight into the pathogenesis of cytokine-induced shock in humans.

Original languageEnglish (US)
Pages (from-to)4943-4951
Number of pages9
JournalJournal of Immunology
Issue number8
StatePublished - Apr 15 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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