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Journal of Lipid Research, Vol. 47, 2382-2391, November 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Fas^lpr mice¹

Paolo Bergamo², Diomira Luongo, Francesco Maurano, Giuseppe Mazzarella, Rosita Stefanile and Mauro Rossi

Istituto di Scienze dell'Alimentazione, Consiglio Nazionale delle Ricerche, 83100 Avellino, Italy

¹ This work is dedicated to the memory of Prof. Arturo Leone, Director of the Istituto di Scienze dell'Alimentazione, deceased December 30, 2005.

Published, JLR Papers in Press, July 28, 2006.

² To whom correspondence should be addressed. e-mail: p.bergamo{at}isa.cnr.it

Conjugated linoleic acid (CLA), a naturally occurring peroxisome proliferator-activated receptor (PPAR) ligand, exhibits proapoptotic, immunomodulatory, and anticancer properties. In this study, we examined the biological effects of CLA administration in the MRL/MpJ-Fas^lpr mouse, an animal model of systemic lupus erythematosus (SLE). We found that CLA exerted apparently opposed activities in in vitro experiments, depending on its concentration: 100 µM CLA downregulated IFN synthesis and cell proliferation of splenocytes, in association with apoptosis induction and a decrease of intracellular thiols (GSH + GSSG), whereas 25 µM CLA did not significantly influence cell proliferation but enhanced the expression of -glutamylcysteine ligase catalytic subunit (GCLC) and intracellular GSH concentration. Interestingly, the antiproliferative effect at 100 µM was not inhibited by the PPAR antagonist GW9662. In vivo, CLA administration drastically reduced SLE signs (splenomegaly, autoantibodies, and cytokine synthesis), a condition paralleled by the enhancement of GCLC expression and intracellular GSH content. Moreover, CLA administration significantly downregulated nuclear factor B activity independent of PPAR activation and apoptosis induction. In conclusion, enhanced GSH content and GCLC expression in CLA-treated mice suggest a novel biochemical mechanism underlying its immunomodulatory activity and the beneficial effects on murine SLE signs.

Supplementary key words autoimmune disease • peroxisome proliferator-activated receptor • -glutamylcysteine ligase

Abbreviations: anti-dsDNA, anti-double-stranded DNA; anti-tTG, anti-tissue transglutaminase; CLA, conjugated linoleic acid; 15dPGJ₂, 15-deoxy-12,14-prostaglandin J₂; GCLC, -glutamylcysteine ligase catalytic subunit; IL, interleukin; MRL/lpr, MRL/MpJ-Fas^lpr; NFB, nuclear factor B; O₂^•–, superoxide anion radical; PPAR peroxisome proliferator-activated receptor ; ROS, reactive oxygen species; SLE, systemic lupus erythematosus

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