Abstract
Monoamine oxidase A (MAO-A) is a mitochondrial flavoenzyme implicated in the pathogenesis of atherosclerosis and inflammation and also in many neurological disorders. MAO-A also has been reported as a potential therapeutic target in prostate cancer. However, the regulatory mechanisms controlling cytokine-induced MAO-A expression in immune or cancer cells remain to be identified. Here, we show that MAO-A expression is co-induced with 15-lipoxygenase (15-LO) in interleukin 13 (IL-13)-activated primary human monocytes and A549 non-small cell lung carcinoma cells. We present evidence that MAO-A gene expression and activity are regulated by signal transducer and activator of transcription 1, 3, and 6 (STAT1, STAT3, and STAT6), early growth response 1 (EGR1), and cAMP-responsive element-binding protein (CREB), the same transcription factors that control IL-13-dependent 15-LO expression. We further established that in both primary monocytes and in A549 cells, IL-13-stimulated MAO-A expression, activity, and function are directly governed by 15-LO. In contrast, IL-13-driven expression and activity of MAO-A was 15-LO-independent in U937 promonocytic cells. Furthermore, we demonstrate that the 15-LO-dependent transcriptional regulation of MAO-A in response to IL-13 stimulation in monocytes and in A549 cells is mediated by peroxisome proliferator-activated receptor γ (PPARγ) and that signal transducer and activator of transcription 6 (STAT6) plays a crucial role in facilitating the transcriptional activity of PPARγ. We further report that the IL-13-STAT6-15-LO-PPARγ axis is critical for MAO-A expression, activity, and function, including migration and reactive oxygen species generation. Altogether, these results have major implications for the resolution of inflammation and indicate that MAO-A may promote metastatic potential in lung cancer cells.
Highlights
Monoamine oxidase A (MAO-A) is a mitochondrial flavoenzyme implicated in the pathogenesis of atherosclerosis and inflammation and in many neurological disorders
As we reported that the interleukin 13 (IL-13)–activated MAO-A gene expression depends on 15-LO and 15-LO generates the PPAR␥ ligand (13S)-HPODE and its stable form (13S)-HODE, we investigated the effect of addition of these fatty acids on the restoration of MAO-A gene expression in those cells that are already treated with the 15-LO antisense to establish a direct role of PPAR␥ and its ligand in IL-13–induced MAO-A expression
We demonstrated that during IL-13 stimulation 15-lipoxygenase and MAO-A are the two strongly up-regulated genes that are co-induced in primary monocytes/macrophages, A549 lung carcinoma cells, and in normal human bronchial epithelial (NHBE) cells
Summary
In human peripheral blood monocytes, IL-13 up-regulates expression of a variety of gene products [1], and one of the most strongly up-regulated proteins is the lipid-peroxidizing enzyme 15-LO [6]. Our data reveal that in presence of Stat decoy ODN, when the interaction between Stat and PPAR␥ is significantly diminished and PPAR␥ DNA-binding activity is markedly reduced, the IL-13–induced MAO-A protein and mRNA expression is almost completely blocked compared with the IL-13–treated positive control ODN, again the function of MAO-A is controlled as evidenced by the significant attenuation of ROS generation level in IL-13– activated monocytes/macrophages, whereas Stat6-scrambled ODN had no effect (Fig. 11B) These data strongly suggest that IL-13 signal transduction uses a distinct 15-LO and PPAR␥-dependent mechanism that is regulated by Stat in A549 cells and in primary monocytes/macrophages to control the IL-13– driven function of MAO-A in tyramine-induced ROS generation
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