The NR4A Orphan Receptor Modulator C-DIM12 Selectively Alters Inflammatory Mediators in Myeloid Cells

Author:

Aldhafiri Sarah1,Marai Mariam23,Ismaiel Mohamed24ORCID,Murphy Brenda24,Giffney Hugh E.1,Hall Thomas J.5,Murphy Evelyn P.6ORCID,Cummins Eoin P.27ORCID,Crean Daniel17

Affiliation:

1. School of Veterinary Medicine, University College Dublin, D04 V1W8 Dublin, Ireland

2. School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland

3. Diabetes and Complication Research Centre (DCRC), Conway Institute of Biomolecular and Biomedical Research, University College Dublin, D04 V1W8 Dublin, Ireland

4. St. Vincent’s University Hospital, D04 T6F4 Dublin, Ireland

5. School of Agriculture and Food Science, University College Dublin, D04 V1W8 Dublin, Ireland

6. School of Medicine, University of Limerick, V94 T9PX Limerick, Ireland

7. Conway Institute of Biomolecular and Biomedical Research, University College Dublin, D04 V1W8 Dublin, Ireland

Abstract

Orphan nuclear receptor subfamily 4A (NR4A) are key regulators of inflammatory responses, largely by their interactions with NF-κB. Over the last decade, several NR4A modulators have been developed, and they are showing potential as therapeutics, although their widespread use in laboratory settings is limited. Here, we have examined, using myeloid cell line THP-1, whether the NR4A modulator 3-[(4-Chlorophenyl)-(1H-indol-3-yl)methyl]-1H-indole (C-DIM12) can alter the inflammatory outcome of six inflammatory ligands: lipopolysaccharide (LPS), tumour necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), flagellin (FL), lipoteichoic acid (LTA), and zymosan (ZY). We demonstrate that C-DIM12 (10 µM) selectively alters the secretion of inflammatory chemokine MCP-1 following exposure to distinct inflammatory ligands in a concentration-dependent manner. Furthermore, data obtained from THP-1 Lucia cell experiments show that 10 µM C-DIM12, and not 1 µM C-DIM12, can significantly attenuate the increased NF-κB transcriptional activity observed following the exposure to several inflammatory ligands (LPS, FL, TNFα, LTA, and ZY). Lastly, experimental analysis confirms that the cellular action(s) of C-DIM12 is independent of changes in metabolic parameters. Thus, these data contribute to the understanding of how the NR4A modulator C-DIM12 alters inflammatory responses in a myeloid cell following exposure to multiple ligands.

Funder

Saudi Arabian Cultural Bureau

Science Foundation Ireland (SFI) Career Development Award

Publisher

MDPI AG

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