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c-di-GMP Induces COX-2 Expression in Macrophages in a STING-Independent Manner
- Source :
- ACS Chemical Biology; September 2021, Vol. 16 Issue: 9 p1663-1670, 8p
- Publication Year :
- 2021
-
Abstract
- Many pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) and lipoteichoic acid, are potent immunostimulatory molecules and promote the expression of cyclooxygenase 2 (COX-2). While the production of COX-2, and ultimately prostaglandin E2, could be protective, persistent induction of COX-2 leads to inflamed environments that can result in septic shock and death. Bacterial derived cyclic dinucleotides (CDNs), c-di-GMP and c-di-AMP, are also PAMPs and have been shown to produce inflamed environments via the production of pro-inflammatory cytokines such as type I interferons. The well-characterized CDN immunostimulatory mechanism involves binding to stimulator of interferon genes (STING), which ultimately results in the phosphorylation of IRF3 or release of NF-κB to promote expression of type I IFN or pro-inflammatory cytokines. In this study, we sought to investigate if CDNs promote COX-2 expression. Using RAW macrophages as a model system, we reveal that c-di-GMP, but not c-di-AMP or the host-derived 2′,3′-cGAMP, promotes COX-2 expression. Using analogues of CDNs, we show that the presence of two guanines and two 3′,5′-phosphodiester linkages are requirements for the promotion of COX-2 expression by cyclic dinucleotides. Both c-di-GMP and LPS inductions of COX-2 expression in RAW macrophages are STING-independent and are regulated by Tpl2-MEK-ERK-CREB signaling; inhibitors of Tpl2, MEK, and ERK could attenuate COX-2 expression promoted by c-di-GMP. This work adds to the growing body of evidence that cyclic dinucleotides regulate pathways other than the STING–TBK1–IRF3 axis. Additionally, the differential COX-2 induction by c-di-GMP but not c-di-AMP or cGAMP suggests that the type and level of inflammation could be dictated by the nucleotide signature of the invading pathogen.
Details
- Language :
- English
- ISSN :
- 15548929 and 15548937
- Volume :
- 16
- Issue :
- 9
- Database :
- Supplemental Index
- Journal :
- ACS Chemical Biology
- Publication Type :
- Periodical
- Accession number :
- ejs57659913
- Full Text :
- https://doi.org/10.1021/acschembio.1c00342