Some fatty acid derivatives, like prostaglandins and thromboxanes, are well known signaling molecules. A more recently recognized, related class of molecules that could have similar functions includes the nitration products of unsaturated fatty acids (nitroalkenes) formed in nitric oxide (NO)-dependent oxidative reactions. In particular, the nitroalkene derivatives of linoleic acid (LNO2) and oleic acid (OA-NO2) are found in human plasma and are thought to regulate physiological functions in multiple cell types. Rather than binding to receptors, though, these molecules are proposed to act by mediating reversible nitroalkylation of glutathione or of Cys or His residues of proteins. Cui et al. now report experiments indicating that LNO2 and OA-NO2 may function as antiinflammatory agents. The authors applied concentrations of LNO2 and OA-NO2 similar to those found in human blood to cultured mouse macrophages and observed dose-dependent decreases in lipopolysaccharide (LPS)-induced cytokine secretion by the cells. The transcription factor NF-κB has a central role in inflammatory responses, and treatment of macrophages with LNO2 or OA-NO2 decreased activation of the transcription factor in response to LPS. Experiments with biotinylated LNO2, OA-NO2, LA (linoleic acid), and OA indicated that LNO2 and OA-NO2, but not LA or OA, associated with the p65 subunit of NF-κB and appeared to modify p65 by covalent nitroalkylation. The nitroalkenes also inhibited adhesion of monocytes to endothelial cells in culture. The authors propose that nitroalkenes like LNO2 and OA-NO2 may prove to be an important class of signaling molecules influencing inflammatory processes.
T. Cui, F. J. Schopfer, J. Zhang, K. Chen, T. Ichikawa, P. R. S. Baker, C. Batthyany, B. K. Chacko, X. Feng, R. P. Patel, A. Agarwal, B. A. Freeman, Y. E. Chen, Nitrated fatty acids: Endogenous anti-inflammatory signaling mediators. J. Biol. Chem. 281, 35686-35698 (2006). [Abstract] [Full Text]