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3,3'-diindolylmethane ameliorates experimental autoimmune encephalomyelitis by promoting cell cycle arrest and apoptosis in activated T cells through microRNA signaling pathways.

Abstract
3,3'-Diindolylmethane (DIM) is a naturally derived indole found in cruciferous vegetables that has great potential as a novel and effective therapeutic agent. In the current study, we investigated the effects of DIM post-treatment on the regulation of activated T cells during the development of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. We demonstrated that the administration of DIM 10 days after EAE induction was effective at ameliorating disease parameters, including inflammation and central nervous system cellular infiltration. MicroRNA (miRNA) microarray analysis revealed an altered miRNA profile in brain infiltrating CD4(+) T cells following DIM post-treatment of EAE mice. Additionally, bioinformatics analysis suggested the involvement of DIM-induced miRNAs in pathways and processes that halt cell cycle progression and promote apoptosis. Additional studies confirmed that DIM impacted these cellular processes in activated T cells. Further evidence indicated that DIM treatment significantly upregulated several miRNAs (miR-200c, miR-146a, miR-16, miR-93, and miR-22) in brain CD4(+) T cells during EAE while suppressing their associated target genes. Similarly, we found that overexpression of miR-16 in primary CD4(+) T cells led to significant downregulation of both mRNA and protein levels of cyclin E1 and B-cell lymphoma-2, which play important roles in regulating cell cycle progression and apoptosis. Collectively, these studies demonstrate that DIM post-treatment leads to the amelioration of EAE development by suppressing T-cell responses through the induction of select miRNAs that control cell cycle progression and mediate apoptosis.
AuthorsMichael Rouse, Roshni Rao, Mitzi Nagarkatti, Prakash S Nagarkatti
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 350 Issue 2 Pg. 341-52 (Aug 2014) ISSN: 1521-0103 [Electronic] United States
PMID24898268 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
Chemical References
  • Core Binding Factor Alpha 2 Subunit
  • Indoles
  • MicroRNAs
  • Proto-Oncogene Proteins c-bcl-2
  • Runx1 protein, mouse
  • 3,3'-diindolylmethane
Topics
  • Animals
  • Apoptosis (drug effects)
  • Cell Cycle Checkpoints (drug effects)
  • Cells, Cultured
  • Core Binding Factor Alpha 2 Subunit (physiology)
  • Encephalomyelitis, Autoimmune, Experimental (drug therapy, immunology, pathology)
  • Female
  • Indoles (pharmacology)
  • Lymphocyte Activation (drug effects)
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs (physiology)
  • Proto-Oncogene Proteins c-bcl-2 (analysis)
  • Signal Transduction
  • T-Lymphocytes (immunology)

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