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Published online before print October 17, 2006

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(Journal of Leukocyte Biology. 2007;81:607-622.)
© 2007 by Society for Leukocyte Biology

Pivotal Advance: -Galactosylceramide induces protection against lipopolysaccharide-induced shock

Guido Sireci^*,1, Marco P. La Manna^*, Caterina Di Sano, Diana Di Liberto^*, Steven A. Porcelli, Mitch Kronenberg, Francesco Dieli^* and Alfredo Salerno^*

^* Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Palermo, Italy;
Istituto di Biomedicina e Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Palermo, Italy;
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA; and
La Jolla Institute for Allergy and Immunology, San Diego, Calfornia, USA

¹ Correspondence: Dipartimento di Biopatologia e Metodologie Biomediche, Corso Tukory 211, Palermo 90134, Italy. E-mail: sireci{at}unipa.it

ABSTRACT

–galactosylceramide, a natural killer T cell ligand, and its synthetic homolog, KRN7000, consistently influence IFN- and TNF- 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- and TNF-. 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- and macrophages/TNF--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- and TNF- 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- 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.

Key Words: rodent • cytokines • endotoxin

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