Nancy Bigley (Committee Member), Mauricio Di Fulvio (Committee Member), Courtney Sulentic (Advisor)
Master of Science (MS)
The immunoglobulin heavy chain gene (Igh) in various animal models is regulated by numerous regulatory elements including the 3’Igh regulatory region (3’IghRR). Several transcription factors are involved in modulating the 3’IghRR including the aryl hydrocarbon receptor (AhR). The AhR is a ligand-activated transcription factor that mediates the transcription of genes involved in the metabolism of environmental toxicants such as TCDD. TCDD binds AhR and regulates immunoglobulin (Ig) expression in B cells. This modulation appears to be directly mediated by binding of the AhR to dioxin response elements (DRE) within the 3’IghRR. In human B cells, IgG secretion inhibited by TCDD and increased by chemical antagonist of the AhR (AhRA). AhR can interact with different transcription factors like NFκB and AP-1, and modulate signaling pathways such as Src and Akt pathways. the human CL-01 cells express a nonfunctional transactivation domain (AhR TA) in one of its alleles. Therefore, we hypothesized that in human cells the AhR regulates IGH expression by altering 3’IGHRR activation through both genomic and non-genomic mediated mechanisms. The current study focuses on determining the potential non-genomic effects of the AhR on the activation of cytosolic signaling proteins such as Src and Akt, and transcription factors like NFκB and AP-1. In addition, it evaluates the genomic effects of the nonfunctional AhR TA on the 3’IGHRR reporter activity and evaluates the role of AhR in the effect of the TCDD and AhRA on Ig expressing and 3’IGHRR activity. Our results showed that the AhR has non-genomic effects by activating cytosolic signaling protein like Akt and increasing the Iγ3-3’IGHRR reporter activity in response to AhRA that could lead to an increase in IgG secretion. The nonfunctional AhR TA decreased the AhR binding to DRE sites as demonstrated in a DRE reporter but it did not affect 3’IGHRR activity in response to TCDD or AhRA. AhR knockdown by gene editing demonstrated inhibition of IgG secretion and AhRA had no effect on Iγ3-3’IGHRR activity, supporting the suggested a physiological non-genomic role of the AhR in the expression of IgG. Determining the role of the 3’IGHRR and its potential difference in sensitivity to the AhR could provide new insight into potential environmental triggers of immune disorders and provide new targets for drug development.
Department or Program
Microbiology and Immunology
Year Degree Awarded
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