Cutting edge: IL-15 costimulates the generalized Shwartzman reaction and innate immune IFN-gamma 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-gamma. Such IFN-gamma 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-gamma production in vitro. LPS stimulation of SCID mouse splenocytes resulted in measurable IFN-gamma production, which was reduced when IL-15 was neutralized or IL-2/15Rbeta was blocked. Pretreatment with either anti-IL-2/15Rbeta or anti-IL-15 Abs reduced serum IFN-gamma 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-gamma production and significantly contributes to the lethal Shwartzman reaction.
Fehniger
T A
TA
Department of Internal Medicine, Division of Hematology/Oncology, Comprehensive Cancer Center, Ohio State University, Columbus, USA.
Yu
H
H
Cooper
M A
MA
Suzuki
K
K
Shah
M H
MH
Caligiuri
M A
MA
D000818:Animals; D005260:Female; D007106:Immune Sera / Q000494:pharmacology; D007113:Immunity, Innate; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D051379:Mice; D016513:Mice, SCID; D012333:RNA, Messenger / Q000096:biosynthesis; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors; D012790:Shwartzman Phenomenon / Q000276:immunology* / Q000401:mortality; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
C508025:Il15ra protein, mouse; D007106:Immune Sera; D019409:Interleukin-15; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma