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Molecular Pharmacology

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Research ArticleArticle

The Nurr1 Activator 1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane Blocks Inflammatory Gene Expression in BV-2 Microglial Cells by Inhibiting Nuclear Factor κB

Briana R. De Miranda, Katriana A. Popichak, Sean L. Hammond, Bryce A. Jorgensen, Aaron T. Phillips, Stephen Safe and Ronald B. Tjalkens
Molecular Pharmacology June 2015, 87 (6) 1021-1034; DOI: https://doi.org/10.1124/mol.114.095398
Briana R. De Miranda
Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado (B.R.D.M., K.A.P., S.L.H., B.A.J., A.T.P., R.B.T.); Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)
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Katriana A. Popichak
Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado (B.R.D.M., K.A.P., S.L.H., B.A.J., A.T.P., R.B.T.); Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)
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Sean L. Hammond
Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado (B.R.D.M., K.A.P., S.L.H., B.A.J., A.T.P., R.B.T.); Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)
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Bryce A. Jorgensen
Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado (B.R.D.M., K.A.P., S.L.H., B.A.J., A.T.P., R.B.T.); Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)
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Aaron T. Phillips
Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado (B.R.D.M., K.A.P., S.L.H., B.A.J., A.T.P., R.B.T.); Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)
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Stephen Safe
Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado (B.R.D.M., K.A.P., S.L.H., B.A.J., A.T.P., R.B.T.); Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)
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Ronald B. Tjalkens
Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado (B.R.D.M., K.A.P., S.L.H., B.A.J., A.T.P., R.B.T.); Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas; and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)
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Abstract

NR4A family orphan nuclear receptors are an important class of transcription factors for development and homeostasis of dopaminergic neurons that also inhibit expression of inflammatory genes in glial cells. The identification of NR4A2 (Nurr1) as a suppressor of nuclear factor κB (NF-κB)–related neuroinflammatory genes in microglia and astrocytes suggests that this receptor could be a target for pharmacologic intervention in neurologic disease, but compounds that promote this activity are lacking. Selected diindolylmethane compounds (C-DIMs) have been shown to activate or inactivate nuclear receptors, including Nurr1, in cancer cells and also suppress astrocyte inflammatory signaling in vitro. Based upon these data, we postulated that C-DIM12 [1,1-bis(3′-indolyl)-1-(p-chlorophenyl) methane] would suppress inflammatory signaling in microglia by a Nurr1-dependent mechanism. C-DIM12 inhibited lipopolysaccharide (LPS)–induced expression of NF-κB–regulated genes in BV-2 microglia including nitric oxide synthase (NOS2), interleukin-6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2), and the effects were attenuated by Nurr1-RNA interference. Additionally, C-DIM12 decreased NF-κB activation in NF-κB–GFP (green fluorescent protein) reporter cells and enhanced nuclear translocation of Nurr1 primary microglia. Chromatin immunoprecipitation assays indicated that C-DIM12 decreased lipopolysaccharide-induced p65 binding to the NOS2 promoter and concurrently enhanced binding of Nurr1 to the p65-binding site. Consistent with these findings, C-DIM12 also stabilized binding of the Corepressor for Repressor Element 1 Silencing Transcription Factor (CoREST) and the Nuclear Receptor Corepressor 2 (NCOR2). Collectively, these data identify C-DIM12 as a modulator of Nurr1 activity that results in inhibition of NF-κB–dependent gene expression in glial cells by stabilizing nuclear corepressor proteins, which reduces binding of p65 to inflammatory gene promoters.

Footnotes

    • Received August 12, 2014.
    • Accepted April 6, 2015.
  • This work was supported by grants from the Michael J. Fox Foundation for Parkinson’s Research and the Consolidated Anti-Aging Foundation, and the National Institutes of Health National Institute of Environmental Health Sciences [Grants ES021656, P30-023512].

  • dx.doi.org/10.1124/mol.114.095398.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (6)
Molecular Pharmacology
Vol. 87, Issue 6
1 Jun 2015
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Research ArticleArticle

Novel Diindolylmethane Analogs Inhibit NF-κB in Microglia

Briana R. De Miranda, Katriana A. Popichak, Sean L. Hammond, Bryce A. Jorgensen, Aaron T. Phillips, Stephen Safe and Ronald B. Tjalkens
Molecular Pharmacology June 1, 2015, 87 (6) 1021-1034; DOI: https://doi.org/10.1124/mol.114.095398

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Research ArticleArticle

Novel Diindolylmethane Analogs Inhibit NF-κB in Microglia

Briana R. De Miranda, Katriana A. Popichak, Sean L. Hammond, Bryce A. Jorgensen, Aaron T. Phillips, Stephen Safe and Ronald B. Tjalkens
Molecular Pharmacology June 1, 2015, 87 (6) 1021-1034; DOI: https://doi.org/10.1124/mol.114.095398
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