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Pivotal advance: alpha-galactosylceramide induces protection against lipopolysaccharide-induced shock.

Abstract
alpha-galactosylceramide, a natural killer T cell ligand, and its synthetic homolog, KRN7000, consistently influence IFN-gamma and TNF-alpha release, both mediators of LPS-induced shock. To modify the course of endotoxin shock, we injected KRN7000 at different time points of experimental systemic Shwartzman reaction. Mice treated with KRN7000 survived when it was injected within 2 h before and after LPS challenge. Mice survival was associated with low levels of T helper 1 (Th1) cytokines, such as IFN-gamma and TNF-alpha. By contrast, protection from endotoxin shock was associated with an increase of T helper 2 (Th2) cytokines, like IL-4 and IL-10. A role of Th2 cytokines in counteracting LPS-induced shock was supported by experiments in which the protection against Shwartzman reaction by KRN7000 was abrogated by in vivo coadministration of anti-Th2 cytokines antibodies. In addition, cytofluorimetric analysis showed that surviving animals have higher percentages of NKT-IL-10-positive cells and lower percentages of NKT-IFN-gamma and macrophages/TNF-alpha-stained cells than nonprotected mice. Taken together, our data demonstrate that KRN7000 treatment given at times near LPS challenge is protective for endotoxin shock inhibiting IFN-gamma and TNF-alpha release. Moreover, KRN7000-mediated protection occurs through an increased production of IL-4 and IL-10, which are mainly secreted by NKT cells. Since IFN-gamma release by NKT requires a longer TCR stimulation than that required for Th2 cytokines production, we demonstrate that timing of KRN7000 in vivo exposure affect the pattern of cytokines expression protecting animals by endotoxin shock.
AuthorsGuido Sireci, Marco P La Manna, Caterina Di Sano, Diana Di Liberto, Steven A Porcelli, Mitch Kronenberg, Francesco Dieli, Alfredo Salerno
JournalJournal of leukocyte biology (J Leukoc Biol) Vol. 81 Issue 3 Pg. 607-22 (Mar 2007) ISSN: 0741-5400 [Print] United States
PMID17046969 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cytokines
  • Galactosylceramides
  • Lipopolysaccharides
  • KRN 7000
Topics
  • Animals
  • Cytokines (antagonists & inhibitors, biosynthesis, drug effects)
  • Disease Models, Animal
  • Disease Progression
  • Galactosylceramides (therapeutic use)
  • Killer Cells, Natural (drug effects, immunology)
  • Lipopolysaccharides
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Shock, Septic (chemically induced, prevention & control)
  • Shwartzman Phenomenon (chemically induced, immunology, prevention & control)
  • Structure-Activity Relationship
  • Th1 Cells (drug effects, immunology)
  • Th2 Cells (drug effects, immunology)

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