Ionizing radiation can induce the production of tumor necrosis factor (TNF-α) in a variety of cell types, although the signal transduction pathways that are involved have not been fully elucidated. Recently hydroxy lipids have been implicated in lipopolysaccharide (LPS)-induced expression of TNF-α by macrophages. We hypothesized that irradiation may act through a similar pathway. The effect of irradiation on the production of the linoleic acid derivative 13-hydroxyoctadecadienoate (13-HODE) by murine peritoneal macrophages was therefore examined and correlated with radiation-induced production of TNF-α. We have shown that low to intermediate doses of radiation (0.5-5 Gy) increase levels of 13-HODE, and in particular the free rather than the ester form. Irradiation also "primed" macrophages for elevated production of TNF-α and 13-HODE in response to LPS. Linoleate treatment in vitro and in vivo similarly enhanced the ability of macrophages to make TNF-α in response to LPS. Radiation-induced oxidized derivatives of linoleate may mediate many inflammatory and noninflammatory effects of irradiation. Although the mechanism by which radiation leads to production of oxidized lipid derivatives and how they interact with other elements in the TNF-α pathway have yet to be elucidated fully, our findings suggest an important role for lipid metabolites in radiation-induced signal transduction.

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