Nitrated fatty acids: Endogenous anti-inflammatory signaling mediators.
Nitroalkene derivatives of linoleic acid (LNO2) and oleic acid (OA-NO2) are present; however, their biological functions remain to be fully defined. Herein, we report that LNO2 and OA-NO2 inhibit lipopolysaccharide-induced secretion of proinflammatory cytokines in macrophages independent of nitric oxide formation, peroxisome proliferator-activated receptor-gamma activation, or induction of heme oxygenase-1 expression. The electrophilic nature of fatty acid nitroalkene derivatives resulted in alkylation of recombinant NF-kappaB p65 protein in vitro and a similar reaction with p65 in intact macrophages. The nitroalkylation of p65 by fatty acid nitroalkene derivatives inhibited DNA binding activity and repressed NF-kappaB-dependent target gene expression. Moreover, nitroalkenes inhibited endothelial tumor necrosis factor-alpha-induced vascular cell adhesion molecule 1 expression and monocyte rolling and adhesion. These observations indicate that nitroalkenes such as LNO2 and OA-NO2, derived from reactions of unsaturated fatty acids and oxides of nitrogen, are a class of endogenous anti-inflammatory mediators.
Cui
Taixing
T
Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Schopfer
Francisco J
FJ
Zhang
Jifeng
J
Chen
Kai
K
Ichikawa
Tomonaga
T
Baker
Paul R S
PR
Batthyany
Carlos
C
Chacko
Balu K
BK
Feng
Xu
X
Patel
Rakesh P
RP
Agarwal
Anupam
A
Freeman
Bruce A
BA
Chen
Yuqing E
YE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000737:chemistry; D009584:Nitrogen / Q000737:chemistry; D047495:PPAR gamma / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction
D000893:Anti-Inflammatory Agents; D005227:Fatty Acids; D016328:NF-kappa B; D047495:PPAR gamma; D011994:Recombinant Proteins; D006419:Heme Oxygenase (Decyclizing); D009584:Nitrogen