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Research ArticleCellular and Molecular

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

Gitanjali A. Narayanan, Iain A. Murray, Gowdahalli Krishnegowda, Shantu Amin and Gary H. Perdew
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 345-355; DOI: https://doi.org/10.1124/jpet.112.193482
Gitanjali A. Narayanan
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Iain A. Murray
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Gowdahalli Krishnegowda
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Shantu Amin
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Gary H. Perdew
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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 [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. These results suggest that SAhRMs such as DiMNF have therapeutic potential in regulating the immune response to tumor formation.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grants ES004869, ES019964].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.193482.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    AHR
    aryl hydrocarbon receptor
    SAhRM
    selective AHR modulator
    ARNT
    AHR nuclear translocator
    DRE
    dioxin response element
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    DiMNF
    3′,4′-dimethoxy-α-naphthoflavone
    SGA360
    1-allyl-3–4-dimethoxyphenyl)-7-(trifluromethyl)-1H-indazole
    GNF351
    N-(2-(1H-indol-3-yl)ethyl)-9-isopropyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine
    DMSO
    dimethyl sulfoxide
    IL
    interleukin
    IL1B
    IL-1β
    C3
    complement component 3
    NF-κB
    nuclear factor κB
    CRP
    C-reactive protein
    CFH
    complement factor H
    MAC
    membrane attack complex
    siRNA
    small interfering RNA
    PCR
    polymerase chain reaction
    MOPS
    4-morpholinepropanesulfonic acid
    BSA
    bovine serum albumin
    CRE
    cAMP response element
    CH-223191
    2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide
    RLU
    relative light units
    BGal
    β-galactosidase.

  • Received February 22, 2012.
  • Accepted May 1, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticleCellular and Molecular

Selective Activation of AHR Represses CD55 Expression

Gitanjali A. Narayanan, Iain A. Murray, Gowdahalli Krishnegowda, Shantu Amin and Gary H. Perdew
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 345-355; DOI: https://doi.org/10.1124/jpet.112.193482

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Research ArticleCellular and Molecular

Selective Activation of AHR Represses CD55 Expression

Gitanjali A. Narayanan, Iain A. Murray, Gowdahalli Krishnegowda, Shantu Amin and Gary H. Perdew
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 345-355; DOI: https://doi.org/10.1124/jpet.112.193482
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