NDLI: Adenosine Modulates NR4A Orphan Nuclear Receptors To Attenuate Hyperinflammatory Responses in Monocytic Cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Cummins, Eoin P. Mohan, Helen Murphy, Evelyn P. Bahar, Bojlul McMorrow, Jason P. Crean, Daniel
Description	Country affiliation: Ireland Author Affiliation: Crean D ( UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland); Cummins EP ( Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.); Bahar B ( UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland); Mohan H ( UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland); McMorrow JP ( UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland); Murphy EP ( UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland)
Abstract	Adenosine receptor-mediated regulation of monocyte/macrophage inflammatory responses is critical in the maintenance of tissue homeostasis. In this study, we reveal that adenosine potently modulates the expression of NR4A1, 2, and 3 orphan nuclear receptors in myeloid cells, and this modulation is primarily through the adenosine A2a receptor subtype. We demonstrate that A2a receptor activation of NR4A1-3 receptor synthesis is further enhanced in TLR4-stimulated monocytes. After TLR4 stimulation, NR4A receptor-depleted monocyte/macrophage cells display significantly altered expression of cell-surface markers and produce increased inflammatory cytokine and chemokine secretion rendering the cells an enhanced proinflammatory phenotype. Exposure of TLR4 or TNF- -stimulated monocytes to adenosine analogs directs changes in the expression of MIP-3 and IL-23p19, with NR4A2 depletion leading to significantly enhanced expression of these factors. Furthermore, we establish that nuclear levels of NF-κB/p65 are increased in TLR/adenosine-stimulated NR4A2-depleted cells. We show that, after TLR/adenosine receptor stimulation, NR4A2 depletion promotes significant binding of NF-κB/p65 to a κB consensus binding motif within the MIP-3 proximal promoter leading to increased protein secretion, confirming a pivotal role for NF-κB activity in controlling cellular responses and gene expression outcomes in response to these mediators. Thus, these data demonstrate that during an inflammatory response, adenosine modulation of NR4A receptor activity acts to limit NF-κB-mediated effects and that loss of NR4A2 expression leads to enhanced NF-κB activity and hyperinflammatory responses in myeloid cells.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	4
Volume Number	195
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2015-08-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Adenosine Metabolism Monocytes Immunology Nuclear Receptor Subfamily 4, Group A, Member 1 Animals Cell Line Chemokine Ccl20 Genetics Dna-binding Proteins Gene Expression Regulation Hypersensitivity Inflammation Interleukin-23 Subunit P19 Macrophages Mice Models, Biological Nf-kappa B Nuclear Receptor Subfamily 4, Group A, Member 2 Nuclear Receptor Subfamily 4, Group A, Member 3 Orphan Nuclear Receptors Receptor, Adenosine A2a Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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