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Cutting Edge: IL-15 Costimulates the Generalized Shwartzman Reaction and Innate Immune IFN- Production In Vivo¹

Todd A. Fehniger^2,*,, Haixin Yu^2,*, Megan A. Cooper^*, Kazuhiro Suzuki^*, Manisha H. Shah^* and Michael A. Caligiuri^3,*,

^* Department of Internal Medicine, Division of Hematology/Oncology, and Department of Molecular Virology, Immunology, and Medical Genetics, Division of Human Cancer Genetics, and the Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210

Sequential administration of LPS to SCID mice results in the generalized Shwartzman reaction, manifesting as rapid mortality via cytokine-induced shock. Here we demonstrate that in vivo neutralization of IL-15 before LPS priming significantly reduced lethality in this reaction (p = 0.0172). We hypothesize that LPS priming induces IL-12 and IL-15 that costimulate NK cell-derived IFN-. Such IFN- may then in turn sensitize macrophages to elicit the Shwartzman reaction following a subsequent LPS challenge. Supporting this, IL-12 and IL-15 synergized to induce murine NK cell IFN- production in vitro. LPS stimulation of SCID mouse splenocytes resulted in measurable IFN- production, which was reduced when IL-15 was neutralized or IL-2/15Rß was blocked. Pretreatment with either anti-IL-2/15Rß or anti-IL-15 Abs reduced serum IFN- protein following LPS administration to SCID mice. Collectively, these data provide the first in vivo evidence that IL-15 participates in LPS-induced innate immune IFN- production and significantly contributes to the lethal Shwartzman reaction.