Inverse regulation of lipid‐peroxidizing and hydroperoxyl lipid‐reducing enzymes by interleukins 4 and 13

Abstract

12/15-lipoxygenases and phospholipid hydroperoxide glutathione peroxidases are opposite enzymes balancing the intracellular concentration of hydroperoxy lipids. We studied the regulation of both enzymes by interleukins 4 and 13 and found an inverse response. When human lung carcinoma cells A549 were cultured in vitro in the presence of these cytokines, an up-regulation of the 12/15-lipoxygenase and a down-regulation of the phospholipid hydroperoxide glutathione peroxidase were observed. A similar inverse regulation was found in human peripheral monocytes. Interleukin 4-treated A549 cells exhibited an impaired capability of reducing exogenous hydroperoxyl lipids and their levels of endogenous lipid hydroperoxides were markedly increased. To find out whether these regulatory processes also occur in vivo, arachidonic acid oxygenase and phospholipid hydroperoxide glutathione peroxidase activity was assayed in various tissues of transgenic mice that systemically overexpress interleukin 4. In lung, spleen, kidney, and heart, an increased arachidonic acid oxygenase activity was detected when transgenic mice were compared with inbred controls. The phospholipid hydroperoxide glutathione peroxidase activity was impaired in lung, liver, and spleen of the transgenic animals. These data indicate that lipid-peroxidizing and lipid peroxide-reducing enzymes are inversely regulated in various mammalian cells. Up-regulation of the 12/15-lipoxygenase and simultaneous down-regulation of the phospholipid hydroperoxide glutathione peroxidase may lead to an increased oxidizing potential, which is reflected by an augmented intracellular peroxide tone.

Chronic inflammation and oxidative stress in human carcinogenesis

“…Other cytokines, such as IFN-g, IL-6 and IL-10 did not induce the enzyme. 90,91 Experiments with human epidermoid carcinoma A431 cells that were transfected with the cDNA sequence of cytoplasmic PH-GPx revealed that PH-GPx downregulates the 12-LOX activity. 92 In animals, platelets 12-LOX, 15-LOX and COX-2 are more sensitive to PH-GPx inhibition than do 5-LOX and COX-1, which are more resistant.…”

“…When the human lung carcinoma cell line A549 is exposed to IL-4 and 13, an upregulation of the 12/ 15-LOX and a downregulation of the PH-GPx are observed. 90,91 Mitochondrial PH-GPx protects from cell death induced by phospholipid hydroperoxidation triggered by photodynamic therapy. 97 Likewise, 2 arsenic compounds, arsenic trioxide and arsenic disulfide, employed against acute promyelocytic leukemia, induce apoptosis in leukemia cells 98 by inhibiting PH-GPx expression.…”

Overexpression of Phospholipid Hydroperoxide Glutathione Peroxidase Modulates Acetyl-CoA, 1-O-Alkyl-2-lyso-sn-glycero-3-phosphocholine Acetyltransferase Activity

“…Thus, antioxidant effectors could influence the multiple intracellular events that involve ROS production. Supporting this is that Schnurr et al (67) reported that IL-4-and IL-13-treated A549 cells up-regulate 12/15-lipoxygenase and down-regulate PHGPx, resulting markedly increased levels of endogenous lipid peroxides. They suggested that the generation of hydroperoxides and peroxide-reducing enzymes is inversely regulated.…”

Dietary Lipids, Cell Adhesion and Breast Cancer Metastasis

“…In fact, we observed a significant decrease in cellular glutathione content and increased ratio between oxidized and reduced glutathione in peripheral endothelial cells exposed to this fatty acid [20]. In addition to linoleic acid-induced activation of NF-KB, we have evidence that treatment with this fatty acid can markedly stimulate NF-«B-dependent transcription [14,44]. However, our earlier reports on vascular effects of linoleic acid have been based on cells isolated from major vascular vessels, such as pulmonary artery [14,20,33,38,44] or urn-bilical veins [22,32,34].…”

“…In addition to linoleic acid-induced activation of NF-KB, we have evidence that treatment with this fatty acid can markedly stimulate NF-«B-dependent transcription [14,44]. However, our earlier reports on vascular effects of linoleic acid have been based on cells isolated from major vascular vessels, such as pulmonary artery [14,20,33,38,44] or urn-bilical veins [22,32,34]. It is well known that endothelial cells from different tissues and vessels can differ markedly in their structure and functions [45].…”