Selective Modulation of the AH Receptor in Repression of Cytokine-Induced Complement Factor Gene Expression

Open Access
Author:
Narayanan, Gitanjali A
Area of Honors:
Toxicology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Gary H Perdew, Thesis Supervisor
  • James Endres Howell, Honors Advisor
  • Adam Bleier Glick, Faculty Reader
Keywords:
  • AHR
  • CD55
  • Complement
Abstract:
Modulation of aryl hydrocarbon receptor (AHR) activity by a class of ligands termed selective AHR modulators (SAhRMs) has been demonstrated to attenuate pro-inflammatory gene expression and signaling, including repression of cytokine-mediated induction of acute phase genes (e.g, Saa1) . These effects are observed to occur through an AHR-dependent mechanism that does not require canonical signaling through dioxin response elements (DREs). Previously, we have demonstrated that the SAhRM, 3´,4´-dimethoxy-α-napthoflavone (DiMNF) can repress the cytokine-mediated induction of complement factor genes. Here, we report that activation of the AHR with DiMNF can suppress the cytokine-mediated induction of the membrane complement regulatory protein (mCRP) CD55, which, when expressed on host cells, facilitates the decay of the complement component 3 (C3) convertase, thereby protecting the cell from complement mediated lysis. Furthermore, we also demonstrate that the cytokine-mediated expression of the mCRP, CD46, is also repressed by DiMNF. Tumor cells often exhibit elevated CD55 and CD46 expression on the cell surface in the inflammatory microenvironment of the tumor and it is thought that such enhanced expression represents a means of escaping immune surveillance. DiMNF can repress the cytokine-mediated induction of CD55 mRNA and protein. Luciferase reporter analysis have identified possible response elements on the CD55 promoter, which may be targets for this repression. CD97 is the receptor for CD55 and this binding has been shown to play a role in the development of inflammation and leukocyte trafficking, as well as stimulate tumor cell migration and angiogenesis. We report here that DiMNF is capable of repressing cytokine-mediated induction of CD97 expression in addition to CD46 and CD55. A C3 deposition assay with [125I]-C3 revealed that repression of cytokine-mediated CD55 expression by DiMNF led to an increase of C3 deposition on the surface of Huh7 cells, which would likely stimulate the formation of the membrane attack complex (MAC) and lead to complement-mediated lysis. We thereby suggest that SAhRMs such as DiMNF have therapeutic potential in regulating the immune response to tumor formation.