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Selective aryl hydrocarbon receptor modulator-mediated repression of CD55 expression induced by cytokine exposure.

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-?-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.

SUBMITTER: Narayanan GA

PROVIDER: S-EPMC3400802 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other

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Selective aryl hydrocarbon receptor modulator-mediated repression of CD55 expression induced by cytokine exposure.

Narayanan Gitanjali A GA Murray Iain A IA Krishnegowda Gowdahalli G Amin Shantu S Perdew Gary H GH

The Journal of pharmacology and experimental therapeutics 20120502 2

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- ...[more]

PMID: 22553215

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Project description:The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, the role of the AHR in normal physiology is still an area of intense investigation. For example, this receptor plays an important role in certain immune responses. We have previously determined that the AHR can mediate repression of acute-phase genes in the liver. For this observation to be therapeutically useful, selective activation of the AHR would likely be necessary. Recently, the selective estrogen receptor ligand WAY-169916 has also been shown to be a selective AHR ligand. WAY-169916 can efficiently repress cytokine-mediated acute-phase gene expression (e.g., SAA1) yet fail to mediate a dioxin response element-driven increase in transcriptional activity. The goals of this study were to structurally modify WAY-169916 to block binding to the estrogen receptor and increase its affinity for the AHR. A number of WAY-169916 derivatives were synthesized and subjected to characterization as AHR ligands. The substitution of a key hydroxy group for a methoxy group ablates binding to the estrogen receptor and increases its affinity for the AHR. The compound 1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA 360), in particular, exhibited essentially no AHR agonist activity yet was able to repress cytokine-mediated SAA1 gene expression in Huh7 cells. SGA 360 was tested in a 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated ear inflammatory edema model using C57BL6/J and Ahr(-/-) mice. Our findings indicate that SGA 360 significantly inhibits TPA-mediated ear swelling and induction of a number of inflammatory genes (e.g., Saa3, Cox2, and Il6) in C57BL6/J mice. In contrast, SGA 360 had no effect on TPA-mediated ear swelling or inflammatory gene expression in Ahr(-/-) mice. Collectively, these results indicate that SGA 360 is a selective Ah receptor modulator (SAhRM) that exhibits anti-inflammatory properties in vivo.

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Selective aryl hydrocarbon receptor modulator-mediated repression of CD55 expression induced by cytokine exposure.

Publications

Selective aryl hydrocarbon receptor modulator-mediated repression of CD55 expression induced by cytokine exposure.

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