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.