Selective Aryl Hydrocarbon Receptor Modulator-Mediated Repression of CD55 Expression Induced by Cytokine Exposure (original) (raw)

Research ArticleCellular and Molecular

Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 345-355; DOI: https://doi.org/10.1124/jpet.112.193482

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.

• ↵ 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)-1_H_-indazole
  GNF351
  _N_-(2-(1_H_-indol-3-yl)ethyl)-9-isopropyl-2-(5-methylpyridin-3-yl)-9_H_-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-2_H_-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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