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Mediator MED23 regulates inflammatory responses and liver fibrosis
- Source :
- PLoS Biology, Vol 17, Iss 12, p e3000563 (2019), PLoS Biology
- Publication Year :
- 2019
- Publisher :
- Public Library of Science (PLoS), 2019.
-
Abstract
- Liver fibrosis, often associated with cirrhosis and hepatocellular carcinomas, is characterized by hepatic damage, an inflammatory response, and hepatic stellate cell (HSC) activation, although the underlying mechanisms are largely unknown. Here, we show that the transcriptional Mediator complex subunit 23 (MED23) participates in the development of experimental liver fibrosis. Compared with their control littermates, mice with hepatic Med23 deletion exhibited aggravated carbon tetrachloride (CCl4)-induced liver fibrosis, with enhanced chemokine production and inflammatory infiltration as well as increased hepatocyte regeneration. Mechanistically, the orphan nuclear receptor RAR-related orphan receptor alpha (RORĪ±) activates the expression of the liver fibrosis-related chemokines C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10), which is suppressed by the Mediator subunit MED23. We further found that the inhibition of Ccl5 and Cxcl10 expression by MED23 likely occurs because of G9a (also known as euchromatic histone-lysine N-methyltransferase 2 [EHMT2])-mediated H3K9 dimethylation of the target promoters. Collectively, these findings reveal hepatic MED23 as a key modulator of chemokine production and inflammatory responses and define the MED23-CCL5/CXCL10 axis as a potential target for clinical intervention in liver fibrosis.<br />Liver fibrosis is characterized by hepatic damage, an inflammatory response, and hepatic stellate cell activation, but the underlying mechanisms remain unclear. This study reveals that the transcriptional Mediator subunit MED23 regulates the pathogenesis of liver fibrosis by controlling the production of inflammatory cytokines such as CCL5 and CXCL10.
- Subjects :
- Liver Cirrhosis
Male
0301 basic medicine
Chemokine
Cirrhosis
Physiology
Pathology and Laboratory Medicine
Biochemistry
White Blood Cells
Mice
0302 clinical medicine
Animal Cells
Immune Physiology
Medicine and Health Sciences
Small interfering RNAs
Biology (General)
Immune Response
Carbon Tetrachloride
Chemokine CCL5
Mice, Knockout
Orphan receptor
Innate Immune System
Mediator Complex
biology
Liver Diseases
Chemotaxis
General Neuroscience
Nuclear Receptor Subfamily 1, Group F, Member 1
Nucleic acids
Cell Motility
Liver
Liver Fibrosis
Cytokines
Chemokines
Cellular Types
Anatomy
General Agricultural and Biological Sciences
Research Article
QH301-705.5
Immune Cells
Immunology
CCL4
Gastroenterology and Hepatology
General Biochemistry, Genetics and Molecular Biology
CCL5
Cell Line
03 medical and health sciences
Signs and Symptoms
Mediator
Diagnostic Medicine
Genetics
medicine
Animals
CXCL10
Non-coding RNA
Inflammation
Blood Cells
General Immunology and Microbiology
Macrophages
Biology and Life Sciences
Cell Biology
Molecular Development
medicine.disease
Gene regulation
Chemokine CXCL10
Disease Models, Animal
030104 developmental biology
Immune System
Hepatocytes
biology.protein
Hepatic stellate cell
Cancer research
RNA
Gene expression
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- ISSN :
- 15457885
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- PLOS Biology
- Accession number :
- edsair.doi.dedup.....86f775cb5757961e9a6ebd05e878ae08