Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Fas(lpr) mice.
Conjugated linoleic acid (CLA), a naturally occurring peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 microM CLA downregulated IFN gamma synthesis and cell proliferation of splenocytes, in association with apoptosis induction and a decrease of intracellular thiols (GSH + GSSG), whereas 25 microM CLA did not significantly influence cell proliferation but enhanced the expression of gamma-glutamylcysteine ligase catalytic subunit (GCLC) and intracellular GSH concentration. Interestingly, the antiproliferative effect at 100 microM was not inhibited by the PPAR gamma 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 kappaB activity independent of PPAR gamma 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.
Bergamo
Paolo
P
Istituto di Scienze dell'Alimentazione, Consiglio Nazionale delle Ricerche, Avellino, Italy. p.bergamo@isa.cnr.it
Luongo
Diomira
D
Maurano
Francesco
F
Mazzarella
Giuseppe
G
Stefanile
Rosita
R
Rossi
Mauro
M
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D016328:NF-kappa B / Q000378:metabolism; D009929:Organ Size; D047495:PPAR gamma / Q000378:metabolism; D017382:Reactive Oxygen Species; D013154:Spleen / Q000166:cytology / Q000196:embryology / Q000378:metabolism
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D016207:Cytokines; D044243:Linoleic Acids, Conjugated; D016328:NF-kappa B; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D007371:Interferon-gamma; D005978:Glutathione