Aryl-hydrocarbon receptor dysregulation and its correlation with immunomodulatory markers in COVID-19 patients

Inflammopharmacology. 2025 Jul;33(7):4115-4124. doi: 10.1007/s10787-025-01828-5. Epub 2025 Jul 1.

Abstract

Introduction: The COVID-19 pandemic with various clinical symptoms has posed significant challenges to the healthcare system. The aryl-hydrocarbon receptor (AhR), a transcription factor that can be activated by both external and internal ligands, may play a role in the regulation of pro-inflammatory cytokines, including interleukin (IL)-6. Additionally, indoleamine-2,3-dioxygenase (IDO)-1 is thought to have an immunomodulatory role and provides kynurenine, an AhR agonist. This research aimed to examine the alteration of AhR and IDO-1 gene expression in patients diagnosed with COVID-19 as well as evaluate their correlation with IL-6 and interferon (IFN)-α serum levels.

Methods: A total of 30 patients diagnosed with COVID-19, along with 30 healthy individuals matched for age and gender, were chosen to serve as the control group. The gene expressions of AhR and IDO-1 were assessed using RT-PCR as well as the serum concentration of IL-6 was measured using ELISA techniques.

Results: The results showed an increased level of AhR gene expression (p value: 0.017), and elevated serum levels of IL-6 (p value: 0.044) in the patients with COVID analyzed alongside the control group. However, IDO-1 gene expression was slightly downregulated. IFN-α serum levels were comparable between the two groups. AhR gene expression had a weak negative correlation with IDO-1 expression. Neither IL-6 nor IFN-α showed a correlation with AhR expression; nonetheless, IL-6 demonstrated an increasing pattern by disease severity.

Conclusion: This study's outcomes revealed a dysregulated expression of AhR and IDO-1 in COVID-19 patients. IL-6 was elevated, but IDO-1 as an immunomodulatory molecule was suppressed. Besides, AhR expression showed no correlation with IDO-1, IL-6, or IFN-α levels.

Keywords: Aryl hydrocarbon receptor; COVID-19; Indoleamin2,3-dioxygenase-1; Interferon-alpha; Interleukin-6.

MeSH terms

  • Adult
  • Aged
  • Basic Helix-Loop-Helix Proteins* / genetics
  • Biomarkers / blood
  • Biomarkers / metabolism
  • COVID-19* / blood
  • COVID-19* / genetics
  • COVID-19* / immunology
  • Case-Control Studies
  • Female
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase* / blood
  • Indoleamine-Pyrrole 2,3,-Dioxygenase* / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase* / metabolism
  • Interferon-alpha / blood
  • Interleukin-6 / blood
  • Male
  • Middle Aged
  • Receptors, Aryl Hydrocarbon* / genetics
  • Receptors, Aryl Hydrocarbon* / metabolism
  • SARS-CoV-2

Substances

  • Receptors, Aryl Hydrocarbon
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interleukin-6
  • Interferon-alpha
  • Biomarkers
  • Basic Helix-Loop-Helix Proteins
  • IDO1 protein, human
  • AHR protein, human
  • IL6 protein, human