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Title: A novel diindolylmethane analog, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane, inhibits the tumor necrosis factor-induced inflammatory response in primary murine synovial fibroblasts through a Nurr1-dependent mechanism.

Authors: Afzali, Maryam F; Popichak, Katriana A; Burton, Lindsey H; Klochak, Anna L; Wilson, William J; Safe, Stephen; Tjalkens, Ronald B; Legare, Marie E

Published In Mol Immunol, (2018 09)

Abstract: The progression of rheumatoid arthritis involves the thickening of the synovial lining due to the proliferation of fibroblast-like synoviocytes (FLS) and infiltration by inflammatory cells. Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine involved in progression of the disease. Under rheumatoid conditions, FLS express the tumor necrosis factor (TNF)-recognition complex (TNFR1, TNFR2, VCAM-1 and ICAM-1), which induces local macrophage activation and leads to downstream nuclear factor κB (NF-κB) signaling. The NF-κB-regulated inflammatory gene, cyclooxygenase (COX), increases synthesis of prostaglandins that contribute to the propagation of inflammatory damage within the joint. Because the nuclear orphan receptor, NR4A2 (Nurr1), can negatively regulate NF-κB-dependent inflammatory gene expression in macrophages, we postulated that activation of this receptor by the Nurr1 ligand 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane (C-DIM12) would modulate inflammatory gene expression in synovial fibroblasts by inhibiting NF-κB. Treatment with C-DIM12 suppressed TNFα-induced expression of adhesion molecules and NF-κB regulated genes in primary synovial fibroblasts including vascular adhesion molecule 1 (VCAM-1), PGE2 and COX-2. Immunofluorescence studies indicated that C-DIM12 did not prevent translocation of p65 and stabilized nuclear localization of Nurr1 in synovial fibroblasts. Knockdown of Nurr1 expression by RNA interference prevented the inhibitory effects of C-DIM12 on inflammatory gene expression, indicating that the anti-inflammatory effects of this compound are Nurr1-dependent. Collectively, these data suggest that this receptor may be a viable therapeutic target in RA.

PubMed ID: 29870816 Exiting the NIEHS site

MeSH Terms: Animals; Cells, Cultured; Fibroblasts/drug effects; Fibroblasts/metabolism*; Fibroblasts/pathology; Gene Expression Regulation/drug effects; Immunophenotyping; Indoles/pharmacology*; Inflammation/genetics; Inflammation/pathology; Intercellular Adhesion Molecule-1/metabolism; Methane; Mice, Inbred C57BL; Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism*; Synovial Membrane/pathology*; Transcription Factor RelA/metabolism; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1/metabolism

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