Hydroxychloroquine attenuates double-stranded RNA-stimulated hyper-phosphorylation of tristetraprolin/ZFP36 and AU-rich mRNA stabilization.
Edward G HittiZeyad MuazzenWalid MoghrabiSuhad Al-YahyaKhalid S A KhabarPublished in: Immunology (2024)
The human innate immune system recognizes dsRNA as a pathogen-associated molecular pattern that induces a potent inflammatory response. The primary source of pathogenic dsRNA is cells infected with replicating viruses, but can also be released from uninfected necrotic cells. Here, we show that the dsRNA poly(I:C) challenge in human macrophages activates the p38 MAPK-MK2 signalling pathway and subsequently the phosphorylation of tristetraprolin (TTP/ZFP36). The latter is an mRNA decay-promoting protein that controls the stability of AU-rich mRNAs (AREs) that code for many inflammatory mediators. Hydroxychloroquine (HCQ), a common anti-malaria drug, is used to treat inflammatory and autoimmune disorders and, controversially, during acute COVID-19 disease. We found that HCQ reduced the dsRNA-dependent phosphorylation of p38 MAPK and its downstream kinase MK2. Subsequently, HCQ reduced the abundance and protein stability of the inactive (phosphorylated) form of TTP. HCQ reduced the levels and the mRNA stability of poly (I:C)-induced cytokines and inflammatory mRNAs like TNF, IL-6, COX-2, and IL-8 in THP-1 and primary blood monocytes. Our results demonstrate a new mechanism of the anti-inflammatory role of HCQ at post-transcriptional level (TTP phosphorylation) in a model of dsRNA activation, which usually occurs in viral infections or RNA release from necrotic tissue.
Keyphrases
- protein kinase
- binding protein
- induced apoptosis
- endothelial cells
- inflammatory response
- oxidative stress
- anti inflammatory
- cell cycle arrest
- sars cov
- drug induced
- coronavirus disease
- high glucose
- immune response
- rheumatoid arthritis
- gene expression
- sensitive detection
- induced pluripotent stem cells
- endoplasmic reticulum stress
- multiple sclerosis
- intensive care unit
- protein protein
- amino acid
- lipopolysaccharide induced
- emergency department
- nucleic acid
- liver failure
- cell death
- reduced graphene oxide
- hiv infected
- transcription factor
- diabetic rats
- small molecule
- adverse drug
- microbial community
- aortic dissection
- acute respiratory distress syndrome
- genetic diversity
- extracorporeal membrane oxygenation
- single molecule
- quantum dots