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

Author:

Ferreira Ana M.1,Ferrari Mariana I.1,Trostchansky Andrés2,Batthyany Carlos23,Souza José M.2,Alvarez María N.2,López Gloria V.4,Baker Paul R. S.3,Schopfer Francisco J.3,O'Donnell Valerie5,Freeman Bruce A.3,Rubbo Homero2

Affiliation:

1. Department of Immunology, Faculty of Sciences, University of the Republic, Montevideo 11400, Uruguay

2. Department of Biochemistry, Center for Free Radical and Biomedical Research, Faculty of Medicine, University of the Republic, Montevideo 11800, Uruguay

3. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, U.S.A.

4. Department of Organic Chemistry, Faculty of Sciences, University of the Republic, Montevideo 11800, Uruguay

5. Department of Medical Biochemistry, University of Wales College of Medicine, Cardiff CF14 4XN, U.K.

Abstract

Nitroalkene derivatives of fatty acids act as adaptive, anti-inflammatory signalling mediators, based on their high-affinity PPARγ (peroxisome-proliferator-activated receptor γ) 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 CLNO2 (cholesteryl-nitrolinoleate). CLNO2 levels were found to increase ∼20-fold 24 h after macrophage activation with Escherichia coli lipopolysaccharide plus interferon-γ; this response was concurrent with an increase in the expression of NOS2 (inducible nitric oxide synthase) and was inhibited by the •NO (nitric oxide) inhibitor L-NAME (NG-nitro-L-arginine methyl ester). Macrophage (J774.1 and bone-marrow-derived cells) inflammatory responses were suppressed when activated in the presence of CLNO2 or LNO2 (nitrolinoleate). This included: (i) inhibition of NOS2 expression and cytokine secretion through PPARγ and •NO-independent mechanisms; (ii) induction of haem oxygenase-1 expression; and (iii) inhibition of NF-κB (nuclear factor κB) activation. Overall, 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.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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