Aryl hydrocarbon receptor agonists upregulate VEGF secretion from bronchial epithelial cells

Tsai, Mei Ling; Wang, Tsu‐Nai; Lin, Yi-Shiuan; Kuo, Po‐Lin; Hsu, Ya‐Ling; Huang, Ming‐Shyan

doi:10.1007/s00109-015-1304-0

Cited by 31 publications

(16 citation statements)

References 40 publications

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“…Previous evidences showed that STAT3 activation regulated downstream genes by AhR ligands including TCDD ( 45 ), indoxyl sulfate ( 46 ), and β-naphthoflavone ( 47 ). However, the current results showed that ligand-independent activation of AhR could efficiently mobilize LPS-stimulated STAT3.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway

et al. 2018

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The aryl hydrocarbon receptor (AhR) is an important immune regulator with a role in inflammatory response. However, the role of AhR in IL-10 production by inflammatory macrophages is currently unknown. In this study, we investigated LPS-induced IL-10 expression in macrophages from AhR-KO mice and AhR-overexpressing RAW264.7 cells. AhR was highly expressed after LPS stimulation through NF-κB pathway. Loss of AhR resulted in reduced IL-10 expression in LPS-induced macrophages. Moreover, the IL-10 expression was elevated in LPS-induced AhR-overexpressing RAW264.7 cells. Maximal IL-10 expression was dependent on an AhR non-genomic pathway closely related to Src and STAT3. Furthermore, AhR-associated Src activity was responsible for tyrosine phosphorylation of STAT3 and IL-10 expression by inflammatory macrophages. Adoptive transfer of AhR-expressing macrophages protected mice against LPS-induced peritonitis associated with high IL-10 production. In conclusion, we identified the AhR-Src-STAT3-IL-10 signaling pathway as a critical pathway in the immune regulation of inflammatory macrophages, It suggests that AhR may be a potential therapeutic target in immune response.

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Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway

et al. 2018

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“…In accordance with a recent paper on gene expression modulation after PM exposure [ 43 ], our data have shown that diesel exposure regulates many NFE2L2 target genes involved in glutathione synthesis ( GCLM ), cysteine-glutamate transporter ( SLC7A11 ) and antioxidant response ( HMOX1 , TXNRD1 , and NQO1 ). VEGF ( VEGFA ) is a pro-angiogenic factor with multifunctional roles, including the regulation of both physiological and pathological angiogenesis and vascular remodeling, promoting endothelial cells proliferation and cell migration [ 44 , 45 ]. It has been reported that an increased expression of VEGF, at the mRNA and protein level, in A549 and BEAS-2B cells, occurs after the exposure to external stimuli such as IL1B , TNF-α and lipopolysaccharide (LPS) [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of human bronchial epithelial cell BEAS-2B exposed to diesel and biomass ultrafine particles

et al. 2018

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BackgroundEmissions from diesel vehicles and biomass burning are the principal sources of primary ultrafine particles (UFP). The exposure to UFP has been associated to cardiovascular and pulmonary diseases, including lung cancer. Although many aspects of the toxicology of ambient particulate matter (PM) have been unraveled, the molecular mechanisms activated in human cells by the exposure to UFP are still poorly understood. Here, we present an RNA-seq time-course experiment (five time point after single dose exposure) used to investigate the differential and temporal changes induced in the gene expression of human bronchial epithelial cells (BEAS-2B) by the exposure to UFP generated from diesel and biomass combustion. A combination of different bioinformatics tools (EdgeR, next-maSigPro and reactome FI app-Cytoscape and prioritization strategies) facilitated the analyses the temporal transcriptional pattern, functional gene set enrichment and gene networks related to cellular response to UFP particles.ResultsThe bioinformatics analysis of transcriptional data reveals that the two different UFP induce, since the earliest time points, different transcriptional dynamics resulting in the activation of specific genes. The functional enrichment of differentially expressed genes indicates that the exposure to diesel UFP induces the activation of genes involved in TNFα signaling via NF-kB and inflammatory response, and hypoxia. Conversely, the exposure to ultrafine particles from biomass determines less distinct modifications of the gene expression profiles. Diesel UFP exposure induces the secretion of biomarkers associated to inflammation (CCXL2, EPGN, GREM1, IL1A, IL1B, IL6, IL24, EREG, VEGF) and transcription factors (as NFE2L2, MAFF, HES1, FOSL1, TGIF1) relevant for cardiovascular and lung disease. By means of network reconstruction, four genes (STAT3, HIF1a, NFKB1, KRAS) have emerged as major regulators of transcriptional response of bronchial epithelial cells exposed to diesel exhaust.ConclusionsOverall, this work highlights modifications of the transcriptional landscape in human bronchial cells exposed to UFP and sheds new lights on possible mechanisms by means of which UFP acts as a carcinogen and harmful factor for human health.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4679-9) contains supplementary material, which is available to authorized users.

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“…2c). Multiplex analysis of intratumoral cytokines revealed reduced levels of T cell-related cytokines, such as IFNγ, CXCL9, CCL5/RANTES and IL-15, but increased VEGF, a known AHR-responsive gene 18 ( Supplementary Fig. 2d).…”

Section: Ahr Expression Is Associated With Immunosuppression In Humanmentioning

confidence: 99%

Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine

et al. 2020

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Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8 + T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDOoverexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors.

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Aryl hydrocarbon receptor agonists upregulate VEGF secretion from bronchial epithelial cells

Cited by 31 publications

References 40 publications

Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway

Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway

Transcriptional profiling of human bronchial epithelial cell BEAS-2B exposed to diesel and biomass ultrafine particles

Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine

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