Macrophage activation induces formation of the anti-inflammatory lipid cholesteryl-nitrolinoleate

作者：Ferreira Ana M; Ferrari Mariana I; Trostchansky Andres; Batthyany Carlos; Souza Jose M; Alvarez Maria N; Lopez Gloria V; Baker Paul R S; Schopfer Francisco J; O'Donnell Valerie; Freeman Bruce A^*; Rubbo Homero

来源：Biochemical Journal, 2009, 417(1): 223-234.

DOI：10.1042/BJ20080701

• cholesteryl-nitrolinoleate
• haem oxygenase-1
• inducible nitric oxide synthase
• inflammation
• lipid nitration
• macrophage

Nitroalkene derivatives of fatty acids act as adaptive, anti-inflammatory signalling mediators, based on their high-affinity PPAR gamma (peroxisome-proliferator-activated receptor gamma) ligand activity and electrophilic reactivity with proteins, including transcription factors. Although free or esterified lipid nitroalkene derivatives have been detected in human plasma and urine, their generation by inflammatory stimuli has not been reported. In the present Study, We Show increased nitration of cholesteryl linoleate by activated murine J774.1 macrophages, yielding the mononitrated nitroalkene CLNO(2) (cholesteryl-nitrolinoleate). CLNO(2) levels were found to increase similar to 20-fold 24 h after macrophage activation with Escherichia coli lipopolysaccharide Plus interferon-gamma; this response was concurrent with an increase in the expression of NOS2 (inducible nitric oxide synthase) and was inhibited by the (center dot)NO (nitric oxide) inhibitor L-NAME (N(G-)nitro-L-arginine methyl ester). Macrophage (J774.1 and bone-marrow-derived cells) inflammatory responses were suppressed when activated in the presence of CLNO(2) or LNO(2) (nitrolinoleate). This included: (i) inhibition of NOS2 expression and cytokine secretion through PPAR gamma anti (center dot)NO-independent mechanisms; (ii) induction of haem oxygenase-1 expression; and (iii) inhibition of NF-kappa B (nuclear factor kappa B) activation. Over-all, these results suggest that lipid nitration occurs as part of the response of macrophages to inflammatory stimuli involving NOS2 induction and that these by-products of nitro-oxidative reactions may act as novel adaptive down-regulators of inflammatory responses.

• 出版日期2009-1-1