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Cutting Edge: Novel Role of Lipoxygenases in the Inflammatory Response: Promotion of TNF mRNA Decay by 15-Hydroperoxyeicosatetraenoic Acid in a Monocytic Cell Line ¹

Judith V. Ferrante^* and Antonio Ferrante^2,*,

^* Department of Immunopathology, Women’s and Children’s Hospital, North Adelaide, South Australia; and Department of Paediatrics, University of Adelaide, South Australia and School of Pharmaceutical, Molecular and Biomedical Sciences, University of South Australia, North Adelaide, Australia

The metabolism of arachidonic acid via the lipoxygenase and cyclooxygenase pathways generates metabolites that regulate the inflammatory response. Although products of lipoxygenase are classically proinflammatory, recently it has been demonstrated that lipoxins, 15-hydroperoxyeicosatetraenoic acid (15-HPETE) and 15-hydroxyeicosatetraenoic acid exhibit anti-inflammatory activity. We now demonstrate for the first time that 15-HPETE regulates the production of the proinflammatory cytokine TNF posttranscriptionally by promoting degradation of LPS-induced TNFmRNA in a human monocytic cell line, Mono Mac 6. 15-HPETE causes a significant increase in the rate of TNF but not G3PDHmRNA degradation in the presence of the transcription inhibitor, actinomycin D. The decay of TNFmRNA is accelerated 1.7-fold, and its half-life is decreased by 57%. In view of its chemical and physical properties, we propose that 15-HPETE may function by destabilizing TNFmRNA by interaction with a trans-activating protein bound to the AU-rich element of TNFmRNA.

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				C. Marantos, V. Mukaro, J. Ferrante, C. Hii, and A. Ferrante Inhibition of the Lipopolysaccharide-Induced Stimulation of the Members of the MAPK Family in Human Monocytes/Macrophages by 4-Hydroxynonenal, a Product of Oxidized Omega-6 Fatty Acids Am. J. Pathol., October 1, 2008; 173(4): 1057 - 1066. [Abstract] [Full Text] [PDF]