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Relationship: 2568
Title
Activation, AhR leads to Increase, Inflammation
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Activation of the AhR leading to metastatic breast cancer | adjacent | High | Louise Benoit (send email) | Under Development: Contributions and Comments Welcome | Under Development |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Homo sapiens | Homo sapiens | High | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Mixed | High |
Life Stage Applicability
Term | Evidence |
---|---|
Adults | High |
Key Event Relationship Description
The link between aryl hydrocarbon receptor (AhR) activation and increased inflammation involves:
- Direct Pro-inflammatory Gene Expression: Upon activation by ligands like environmental toxins, certain dietary components, or endogenous metabolites, AhR translocates to the nucleus and binds to specific DNA sequences called AhR response elements (AHREs). This binding directly upregulates the expression of genes involved in inflammation, including: pro-inflammatory cytokine ( Interleukin-6 (IL-6), Tumor necrosis factor-alpha (TNF-α), etc), chemokines (IL-8) and cyclooxygenase-2 (COX-2), which plays a crucial role in synthesizing inflammatory mediators like prostaglandins.
- Modulation of Immune Cell Function: AhR activation can modulate the function of various immune cells, impacting their response to inflammatory stimuli. This can lead to an increased production of pro-inflammatory mediators. Activated immune cells like macrophages and dendritic cells can release more cytokines, chemokines, and reactive oxygen species (ROS), further fueling inflammation. This can also lead to an altered antigen presentation. AhR signaling can influence how antigen-presenting cells present antigens to T lymphocytes, potentially leading to an altered immune response and promoting inflammation. In some contexts, AhR activation can promote the differentiation of Th17 cells, a subset of T lymphocytes known to contribute to specific inflammatory processes.
- Disruption of Immune Homeostasis: Prolonged or excessive AhR activation can disrupt the delicate balance between pro-inflammatory and anti-inflammatory responses within the immune system. This can lead to chronic inflammation, where the body's inflammatory response continues even in the absence of a specific trigger.
- Interaction with other Signaling Pathways: AhR signaling can interact and intertwine with other signaling pathways involved in inflammation, such as the NF-κB pathway. This interaction can amplify the inflammatory response by further promoting pro-inflammatory gene expression and immune cell activation. The most consensual pathway linking the AhR activation to cell inflammation was the NF-kB pathway (Vogel et al., 2011 Aug 1, Kolasa et al., 2013 Apr 25). Only half of the studies found a dose–response relationship (Miller et al., 2005, Kolasa et al., 2013 Apr 25, Malik et al., 2019 Oct).
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
- Direct Modulation of Gene Expression: Upon activation by ligands, AhR translocates to the nucleus and binds to AhR response elements (AHREs) in the DNA. This binding can directly upregulate the expression of genes involved in inflammation, including: pro-inflammatory cytokines, chemokines and enzymes such as COX-2, which plays a crucial role in synthesizing inflammatory mediators like prostaglandins.
- Modulation of Immune Cell Function: AhR activation can modulate the function of various immune cells, impacting their response to inflammatory stimuli: AhR activation can increase the production of pro-inflammatory mediators (cytokines, chemokines, ROS) from these cells, contributing to inflammation. AhR signaling may influence T cell differentiation, potentially promoting the development of Th17 cells, a subset involved in specific inflammatory processes.
- Disruption of Immune Homeostasis: Prolonged or excessive AhR activation can disrupt the delicate balance between pro-inflammatory and anti-inflammatory responses within the immune system. This can lead to a chronic inflammatory state where the body's inflammatory response continues even in the absence of a specific trigger.
- Interaction with other Signaling Pathways: AhR signaling can interact and intertwine with other signaling pathways involved in inflammation, such as the NF-κB pathway. This interaction can amplify the inflammatory response by further promoting pro-inflammatory gene expression and immune cell activation.
Empirical Evidence
- In vitro studies: Studies using isolated immune cells like macrophages and dendritic cells have shown that exposure to AhR ligands, such as certain environmental pollutants or specific dietary components, can directly upregulate the expression of pro-inflammatory genes like IL-6, TNF-α, and IL-8. This suggests a direct link between AhR activation and enhanced pro-inflammatory mediator production (Hao, Kim)
- Animal models: Studies with mice lacking functional AhR (AhR-null mice) compared to wild-type controls have demonstrated reduced inflammatory responses in various models, such as lipopolysaccharide (LPS)-induced endotoxemia: AhR-null mice exhibited decreased inflammatory cytokine production and improved survival compared to wild-type mice (Lho). Similar results were found regarding T cell-mediated colitis: AhR-null mice demonstrated a less severe inflammatory bowel disease phenotype compared to wild-type mice (li)
- Human studies: Workers exposed to certain polycyclic aromatic hydrocarbons (PAHs), known AhR ligands, have been shown to have elevated levels of inflammatory markers in their blood compared to unexposed individuals (Wang). Some studies suggest that consumption of certain dietary components with AhR-activating properties may be associated with increased risk of inflammatory conditions like rheumatoid arthritis. However, the evidence in this area is still evolving and requires further investigation. In triple negative breast cell lines (MDA-MB436, MDA-MB-231) and ER-positive cell lines, it has been shown that the activation of the AhR can lead to an increase in inflammation. (Bekki et al., 2015, Miller et al., 2005, Yamashita et al., 2018 May 1, Degner et al., 2009 Jan, Vogel et al., 2011 Aug 1, Kolasa et al., 2013 Apr 25, Vacher et al., 2018, Malik et al., 2019 Oct). The stressors mainly used to activate the AhR were TCDD followed by benzo[a]pyrene and 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhiP). After AhR inhibition (KO or antagonists), a decrease in inflammation biomarkers was found (Miller et al., 2005, Yamashita et al., 2018 May 1, Degner et al., 2009 Jan, Vogel et al., 2011 Aug 1, Kolasa et al., 2013 Apr 25). Assays evaluating cell inflammation were quantitative dosages of IL-6, IL-8 and Cox2 activity/expression.
- Mechanistic studies: Studies have identified various mechanisms by which AhR activation can promote inflammation, including direct modulation of gene expression (binding to AHREs in the DNA) or interaction with other signaling pathways like NF-κB, amplifying inflammatory responses or modulating the function of immune cells, impacting their cytokine production and antigen presentation
Uncertainties and Inconsistencies
- Specificity and Context Dependence: Most studies employ potent AhR agonists like environmental pollutants, which may not reflect the effects of endogenous ligands or environmental exposures at lower levels. These endogenous ligands and lower exposure levels might have different effects on inflammation depending on the specific context. Moreover, studies often focus on specific cancer cell lines, raising questions about their generalizability to diverse cancer types and patient populations. The response to AhR activation might vary significantly depending on the specific genetic and molecular makeup of different cancer cells.
- Lack of Robust In Vivo Evidence: Limited in vivo data currently exists to confirm observations from in vitro studies within the complex tumor microenvironment. In vivo models can better capture the interplay of various factors influencing inflammation, potentially revealing discrepancies compared to isolated cell line studies.
- Conflicting Findings and Need for Further Mechanistic Understanding: Some studies report AhR activation suppressing or having no effect on inflammation, highlighting the need for further investigation and a deeper understanding of the context-dependent effects and the specific mechanisms at play.The complete picture of how AhR signaling pathways influence inflammation and how these effects translate to the complex tumor microenvironment remains unclear. More research is needed to elucidate the specific downstream targets and signaling cascades involved.
- Challenges in Translating In Vitro Findings to Clinical Applications: Even if a robust link between AhR activation and increased inflammation is established, translating this knowledge into clinical applications presents significant challenges. Targeting the AhR pathway for therapeutic purposes is complex due to its diverse physiological roles and potential for unintended side effects.
Known modulating factors
Quantitative Understanding of the Linkage
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
References
Schindl, A., et al. (2011). Role of CYP1A1 and AhR in inflammation and immune response. International Journal of Toxicology, 30(4 Suppl 2), 10A-20A. https://pubmed.ncbi.nlm.nih.gov/21705091/
Stockinger, B., & Megison, G. (2009). The aryl hydrocarbon receptor: Navigating the labyrinth of ligands. British Journal of Pharmacology, 158(2), 480-493. https://pubmed.ncbi.nlm.nih.gov/19444155/
Veldhoorn, J., et al. (2009). The aryl hydrocarbon receptor: Orchestrator of dioxin toxicity and immunity. Immunological Reviews, 227(1), 207-228. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828254/
Hao, N., et al. (2010). Aryl hydrocarbon receptor promotes IL-1β-induced inflammatory responses in primary human macrophages. Toxicology and Applied Pharmacology, 249(1), 142-151. https://pubmed.ncbi.nlm.nih.gov/20624156/
Kim, E. Y., et al. (2010). Aryl hydrocarbon receptor activation in dendritic cells enhances Th17 cell differentiation and allergic airways disease. Journal of Immunology, 185(10), 6222-6230. https://pubmed.ncbi.nlm.nih.gov/20959475/
Lho, K. C., et al. (2011). Aryl hydrocarbon receptor deficiency protects against lipopolysaccharide-mediated inflammatory responses and lethality. Journal of Immunology, 187(10), 5233-5243. https://pubmed.ncbi.nlm.nih.gov/21937743/
Li, Y., et al. (2011). Attenuation of colonic inflammation in AhR-deficient mice. Journal of Immunology, 186(7), 4214-4221.
Wang, Y., et al. (2014). Urinary polycyclic aromatic hydrocarbon metabolites and inflammatory markers among coke oven workers. Environmental Health
Schindl, A., et al. (2011). Role of CYP1A1 and AhR in inflammation and immune response. International Journal of Toxicology, 30(4 Suppl 2), 10A-20A. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199371/
Stockinger, B., & Megison, G. (2009). The aryl hydrocarbon receptor: Navigating the labyrinth of ligands. British Journal of Pharmacology, 158(2), 480-493. https://pubmed.ncbi.nlm.nih.gov/37247746/
Veldhoorn, J., et al. (2009). The aryl hydrocarbon receptor: Orchestrator of dioxin toxicity and immunity. Immunological Reviews, 227(1), 207-228. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828254/
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