In situ generation, metabolism and immunomodulatory signaling actions of nitro-conjugated linoleic acid in a murine model of inflammation
Villacorta L, Minarrieta L, Salvatore S, Khoo N, Rom O, Gao Z, Berman R, Jobbagy S, Li L, Woodcock S, Chen Y, Freeman B, Ferreira A, Schopfer F, Vitturi D
Erschienen in
Redox biology: Volume 15, Page 522-531
Abstract
Conjugated linoleic acid (CLA) is a prime substrate for intra-gastric nitration giving rise to the formation of nitro-conjugated linoleic acid (NO(2)-CLA). Herein, NO(2)-CLA generation is demonstrated within the context of acute inflammatory responses both in vitro and in vivo. Macrophage activation resulted in dose- and time-dependent CLA nitration and also in the production of secondary electrophilic and non-electrophilic derivatives. Both exogenous NO(2)-CLA as well as that generated in situ, attenuated NF-κB-dependent gene expression, decreased pro-inflammatory cytokine production and up-regulated Nrf2-regulated proteins. Importantly, both CLA nitration and the corresponding downstream anti-inflammatory actions of NO(2)-CLA were recapitulated in a mouse peritonitis model where NO(2)-CLA administration decreased pro-inflammatory cytokines and inhibited leukocyte recruitment. Taken together, our results demonstrate that the formation of NO(2)-CLA has the potential to function as an adaptive response capable of not only modulating inflammation amplitude but also protecting neighboring tissues via the expression of Nrf2-dependent genes.
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