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Linoleic Acid, but not Oleic Acid, Upregulates Production of Interleukin-8 by Human Vascular Smooth Muscle Cells via Arachidonic Acid Metabolites Under Conditions of Oxidative Stress

Departments of Obstetrics and Gynecology, and Physiology, Virginia Commonwealth University Medical Center, Richmond, Virginia

Scott W. Walsh, PhD

Departments of Obstetrics and Gynecology, and Physiology, Virginia Commonwealth University Medical Center, Richmond, Virginia; swwalsh{at}vcu.edu

Objective: Preeclampsia is associated with oxidative stress, elevated plasma levels of linoleic acid (LA), and increased vascular smooth muscle expression of the inflammatory chemokine, interleukin-8 (IL-8). We hypothesized that increased levels of LA under conditions of oxidative stress would increased production of IL-8 by vascular smooth muscle cells because LA is the dietary precursor to arachidonic acid (AA) and its metabolites that mediate inflammation. We also hypothesized that oleic acid (OA), which is not metabolized to AA metabolites, would not increase IL-8 under conditions of oxidative stress.

Methods: To test this hypothesis, we cultured placental arterial smooth muscle (PASM) cells with an exidizing solution enriched with LA (OxLA) or OA (OxOA). Media concentrations were analyzed for IL-8 and AA metabolites. Inhibitors were used to block the lipoxygenase and cyclooxygenase pathways.

Results: Exposure of cells to OxLA, but not to OxOA, significantly increased production of IL-8. OxLA also significantly increased production of AA metabolites. Nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway, blocked IL-8 and leukotriene B₄ (LTB₄ production induced by OxLA, whereas indomethacin, an inhibitor of the cyclooxygenase pathway, blocked IL-8, prostaglandin E₂ (PGE₂), and thromboxane B₂ (TXB₂) production. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated gene expression in PASM cells for representative lipoxygenase (LTB₄) and cyclooxygenase (thromboxane) metabolite receptors.

Conclusion: PASM cells produced IL-8 in response to LA, but not OA, under conditions of oxidative stress. The IL-8 response was mediatedby AA metabolites.

Key Words: Linoleic acid • oleic acid • oxidative stress • interleukin-8 • arachidonic acid metabolites • vascular smooth muscle

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