Cutting edge: IL-15 costimulates the generalized Shwartzman reaction and innate immune IFN-γ production in vivo

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-γ. Such IFN-γ 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-γ production in vitro. LPS stimulation of SCID mouse splenocytes resulted in measurable IFN-γ production, which was reduced when IL-15 was neutralized or IL-2/15Rβ was blocked. Pretreatment with either anti-IL-2/15Rβ or anti-IL- 15 Abs reduced serum IFN-γ 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-γ production and significantly contributes to the lethal Shwartzman reaction.