Hydroxychloroquine attenuates double-stranded RNA-stimulated hyper-phosphorylation of tristetraprolin/ZFP36 and AU-rich mRNA stabilization.

Autor: Hitti EG; Department of Molecular Biomedicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia., Muazzen Z; Department of Molecular Biomedicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia., Moghrabi W; Department of Molecular Biomedicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia., Al-Yahya S; Department of Molecular Biomedicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia., Khabar KSA; Department of Molecular Biomedicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Jazyk: angličtina
Zdroj: Immunology [Immunology] 2024 Nov; Vol. 173 (3), pp. 511-519. Date of Electronic Publication: 2024 Jul 24.
DOI: 10.1111/imm.13835
Abstrakt: 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.
(© 2024 The Author(s). Immunology published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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