PARTIAL AGONIST ACTIVATION OF THE ARYL HYDROCARBON RECEPTOR INCREASES EXPRESSION OF EPIDERMAL DIFFERENTIATION GENES AND ATTENUATES INFLAMMATORY GENE EXPRESSION

Open Access
Author:
Alnemri, Angela Grace
Area of Honors:
Toxicology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Gary H. Perdew, Thesis Supervisor
  • Gary H. Perdew, Honors Advisor
  • Andrew Patterson, Faculty Reader
Keywords:
  • Aryl hydrocarbon receptor
  • AHR
  • Chronic inflammatory skin diseases
  • epidermal differentiation
  • inflammation
Abstract:
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor implicated in a diverse set of physiological functions. The AHR is known to play a role in epidermal differentiation as well as inflammation through cross-talk between the AHR signaling pathway and the inflammatory signaling pathway. This research focuses on characterizing partial AHR agonists that aid in increased expression of epidermal differentiation genes and exhibit anti- inflammatory properties. Epidermal differentiation genes encode proteins with skin barrier functions; therefore, their increased regulation may be important in treating skin diseases, such as atopic dermatitis. Furthermore, anti-inflammatory ligands would reduce the inflammation caused by skin diseases and help alleviate the symptoms. A luciferase-based reporter assay under the control of the AHR was used to test whether a series of indazole derivatives exhibited partial AHR agonist activity in Hepa 1.1 and Hep G2 40/6 cells. Mouse primary keratinocytes were used to study the effects of selected partial AHR agonists on AHR target genes, epidermal differentiation genes, and inflammatory genes. The results indicate that several indazole derivatives, especially SGA388, upregulated the expression of epidermal differentiation genes while displaying anti-inflammatory properties in wild-type mouse primary keratinocytes. Expression of epidermal differentiation genes was not induced by select partial AHR agonists in Ahr-/- keratinocytes, indicating that epidermal differentiation gene expression is mediated by the AHR. Furthermore, none of the partial AHR agonists induced significant CYP1A1 enzymatic activity regardless of their effect on Cyp1a1 gene expression. AHR ligands with this pattern of gene expression may warrant further analysis as candidate therapeutics in treating chronic inflammatory skin diseases.