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Selective Aryl Hydrocarbon Receptor Modulator-Mediated Repression of CD55 Expression Induced by Cytokine Exposure

Selective Aryl Hydrocarbon Receptor Modulator-Mediated Repression of CD55 Expression Induced by Cytokine Exposure

Gitanjali A Narayanan, Iain A Murray, Gowdahalli Krishnegowda, Shantu Amin, Gary H Perdew

J Pharmacol Exp Ther. 2012 Aug;342(2):345-55.

PMID: 22553215

Abstract:

Modulation of aryl hydrocarbon receptor (AHR) activity by a class of ligands termed selective AHR modulators (SAhRMs) has been demonstrated to attenuate proinflammatory 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. Previously, we have demonstrated that the SAhRM 3',4'-dimethoxy-α-naphthoflavone (DiMNF) can repress the cytokine-mediated induction of complement factor genes. Here, we report that the activation of the AHR with DiMNF can suppress cytokine-mediated induction of the membrane complement regulatory protein CD55. When CD55 is expressed on host cells, it facilitates the decay of the complement component 3 (C3) convertase, thereby protecting the cell from complement-mediated lysis. Tumor cells often exhibit elevated CD55 expression on the cell surface in the inflammatory microenvironment of the tumor, and such enhanced expression could represent a means of escaping immune surveillance. DiMNF can repress the cytokine-mediated induction of CD55 mRNA and protein. Luciferase reporter analysis has identified possible response elements on the CD55 promoter, which may be targets for this repression. A C3 deposition assay with [(125)I]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. These results suggest that SAhRMs such as DiMNF have therapeutic potential in regulating the immune response to tumor formation.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP14756242	DiMNF		14756-24-2	Price

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