Regulation of monoamine oxidase A (MAO-A) expression, activity, and function in IL-13–stimulated monocytes and A549 lung carcinoma cells

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 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.

The role of monoamine oxidase A in HPV-16 E7-induced epithelial-mesenchymal transition and HIF-1α protein accumulation in non-small cell lung cancer cells

“…Similarly, Wu et al 15 also reported that MAOA induced EMT, thereby promoting prostate cancer growth, invasion, and metastasis. Additionally, it was reported that MAOA might promote the metastatic potential of lung cancer cells 46 . In this study, we demonstrated that HPV-16 E7 oncoprotein enhanced MAOA expression at both protein and mRNA levels (Figure 1 C,D), and MAOA knockout inhibited the migration, invasion, and EMT induced by HPV-16 E7 oncoprotein in A549 and NCI-H460 NSCLC cells (Figure 2 ,3).…”

The MAO Inhibitor Tranylcypromine Alters LPS- and Aβ-Mediated Neuroinflammatory Responses in Wild-type Mice and a Mouse Model of AD

“…Several recent studies have demonstrated that MAO plays an important role in cardiovascular oxidative stress (e.g., ROS) and induction of inflammation by promoting endothelial dysfunction [ 32 , 33 ]. In addition, MAO-A expression, activity, and function are altered in IL-13-induced monocytes and in A549 lung carcinoma cells [ 34 ]. Vega et al found that MAO alters macrophage-inducible nitric oxide synthase gene expression [ 35 ].…”

“…STAT3 is activated by IL-6 in transient inflammatory and proinflammatory states but is activated by IL-10 in long-term inflammatory and anti-inflammatory states; consequently, STAT3 acts as an intersection of pro and anti-inflammatory effects [ 43 ]. Recently, Dhabal et al reported that MAO-A gene expression and activity are regulated by STAT1, STAT3, and STAT6 [ 34 ]. Thus, we anticipated that MAO inhibitor treatment might modulate the STAT signaling pathway to alter LPS-induced microglial and astrocytic inflammatory responses.…”

Paradoxical Effects of a Cytokine and an Anticonvulsant Strengthen the Epigenetic/Enzymatic Avenue for Autism Research

“…But other molecules activated by IL-17 could promote MAOA and therefore be responsible for ASD cases through a mathematical transitive relation . Indeed, MAOA is one of the most strongly upregulated gene within cells activated by the IL-13 anti-inflammatory interleukin (Dhabal et al, 2018 ), which gives the following: (1) IL-13 → MAOA+. Not surprisingly then, elevated gestational IL-13 associated with maternal inflammatory immune response and maternal–fetal cytokine signaling increases the risk for the offspring to develop abnormalities, namely, ASD, hyperactivity, and inattention (Thürmann et al, 2019 ).…”