Editors' ChoiceInflammation

Positive Peroxidation

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Science Signaling  22 Jul 2008:
Vol. 1, Issue 29, pp. ec263
DOI: 10.1126/scisignal.129ec263

Ingestion of the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) reduces inflammation in vivo, which is thought to involve inhibition of nuclear factor κB (NF-κB) signaling; however, the precise mechanisms involved are unknown. To further complicate matters, DHA is highly susceptible to peroxidation by free radicals, which results in the production of a number of bioactive lipid products, thus making it unclear whether DHA or one of its metabolites is the anti-inflammatory agent. The cyclopentenone neuroprostanes (A4/J4-NPs) form one group of DHA metabolites, and Musiek et al. investigated the effects of a synthetic A4/J4-NP called A4-NP on inflammatory responses in the mouse macrophage cell line RAW267.4. They found that pretreatment of RAW267.4 cells with A4-NP dose-dependently blocked lipopolysaccharide (LPS)-induced expression of the genes encoding two proinflammatory proteins, inducible nitric oxide synthase and cyclooxygenase-2. A combination of NF-κB-reporter assays, immunofluorescence staining, and Western blotting analyses demonstrated that A4-NP blocked LPS-induced responses by inhibiting the activity of inhibitor of κB (IκB) kinase β (IKKβ), thus preventing the phosphorylation of IκB and the translocation of NF-κB to the nucleus. However, A4-NP did not inhibit the activity of a mutant IKKβ that lacked Cys179, which suggests that A4-NP forms an adduct with the thiol group of this residue to inactivate IKKβ. Elimination of the bioactivity of A4-NP through chemical reduction or by complex formation with glutathione prevented it from modifying and inhibiting IKKβ activity. The authors also found that A4/J4-NPs were more abundant in the brains of patients with Alzheimer’s disease than in those of controls, which suggests that in vivo oxidation of DHA may contribute to its anti-inflammatory role.

E. S. Musiek, J. D. Brooks, M. Joo, E. Brunoldi, A. Porta, G. Zanoni, G. Vidari, T. S. Blackwell, T. J. Montine, G. L. Milne, B. McLaughlin, J. D. Morrow, Electrophilic cyclopentenone neuroprostanes are anti-inflammatory mediators formed from the peroxidation of the ω-3 polyunsaturated fatty acid docosahexaenoic acid. J. Biol. Chem. 283, 19927-19935 (2008). [Abstract] [Full Text]

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