Back to Search
Start Over
Mechanisms Underlying the Functional Cooperation Between PPARα and GRα to Attenuate Inflammatory Responses.
- Source :
-
Frontiers in immunology [Front Immunol] 2019 Aug 09; Vol. 10, pp. 1769. Date of Electronic Publication: 2019 Aug 09 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- Glucocorticoids (GCs) act via the glucocorticoid receptor (NR3C1, GRα) to combat overshooting responses to infectious stimuli, including lipopolysaccharide (LPS). As such, GCs inhibit the activity of downstream effector cytokines, such as tumor necrosis factor (TNF). PPARα (NR1C1) is a nuclear receptor described to function on the crossroad between lipid metabolism and control of inflammation. In the current work, we have investigated the molecular mechanism by which GCs and PPARα agonists cooperate to jointly inhibit NF-κB-driven expression in A549 cells. We discovered a nuclear mechanism that predominantly targets Mitogen- and Stress-activated protein Kinase-1 activation upon co-triggering GRα and PPARα. In vitro GST-pull down data further support that the anti-inflammatory mechanism may additionally involve a non-competitive physical interaction between the p65 subunit of NF-κB, GRα, and PPARα. Finally, to study metabolic effector target cells common to both receptors, we overlaid the effect of GRα and PPARα crosstalk in mouse primary hepatocytes under LPS-induced inflammatory conditions on a genome-wide level. RNA-seq results revealed lipid metabolism genes that were upregulated and inflammatory genes that were additively downregulated. Validation at the cytokine protein level finally supported a consistent additive anti-inflammatory response in hepatocytes.
- Subjects :
- A549 Cells
Animals
Dexamethasone pharmacology
Glucocorticoids pharmacology
Hepatocytes drug effects
Hepatocytes metabolism
Humans
Lipid Metabolism genetics
Lipopolysaccharides
Male
Mice, Inbred C57BL
NF-kappa B immunology
PPAR alpha agonists
Inflammation immunology
PPAR alpha immunology
Receptors, Glucocorticoid immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 10
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 31447832
- Full Text :
- https://doi.org/10.3389/fimmu.2019.01769