The protective effects of NE 52-QQ57 against interleukin-33-induced inflammatory response in activated synovial mast cells

by Selleckchem | Oct 09 2023

Cytokines-mediated immunity is essential for the pathological development of rheumatoid arthritis (RA). Inhibition of signaling has suggested a potential remedial approach to RA. G protein-coupled receptor 4 (GPR4) has been proven to possess a broad range of physiological functions, but its function in synovial mast cells and RA is less reported. In this study, the protective effects of NE 52-QQ57, a GPR4 antagonist, against interleukin (IL)-33-challenged inflammatory response in activated synovial mast cells were investigated. We report that IL-33 amplified GPR4 expression in HMC-1 mast cells. The GPR4 antagonist NE 52-QQ57 alleviated IL-33-caused secretions of IL-17, interferon-γ, and tumor necrosis factor-α in HMC-1 mast cells. Furthermore, we note that NE 52-QQ57 reduced IL-33-induced expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9. Also, NE 52-QQ57 inhibited cyclooxygenase 2 and prostaglandin E2 expression in IL-33-challenged cells. Also, NE 52-QQ57 ameliorated IL-33-induced oxidative stress by reducing mitochondrial reactive oxygen species and 4-hydroxynonenal. Mechanistically, NE 52-QQ57 mitigated IL-33-induced activation of the p38/nuclear factor-κB signaling pathway. We conclude that targeting GPR4 might be a promising strategy for RA treatment.

Comments:

The passage you provided describes a study investigating the potential therapeutic effects of a G protein-coupled receptor 4 (GPR4) antagonist, NE 52-QQ57, in the context of rheumatoid arthritis (RA). The study focuses on the role of cytokines in RA and explores the function of GPR4 in synovial mast cells.

The researchers found that interleukin-33 (IL-33), a cytokine involved in inflammation, increased the expression of GPR4 in HMC-1 mast cells. By using NE 52-QQ57, a GPR4 antagonist, they observed a reduction in IL-33-induced secretion of IL-17, interferon-γ, and tumor necrosis factor-α in these mast cells. Additionally, NE 52-QQ57 decreased the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, enzymes involved in tissue degradation in RA. The antagonist also inhibited the expression of cyclooxygenase 2 and prostaglandin E2, which are associated with inflammation. Furthermore, NE 52-QQ57 demonstrated a protective effect against oxidative stress induced by IL-33, reducing the levels of mitochondrial reactive oxygen species and 4-hydroxynonenal, a marker of oxidative damage.

Mechanistically, NE 52-QQ57 was found to mitigate the activation of the p38/nuclear factor-κB signaling pathway, which is involved in inflammation. Based on these findings, the researchers propose that targeting GPR4 could be a promising therapeutic approach for the treatment of rheumatoid arthritis.

It's important to note that the passage you provided appears to be an excerpt from a scientific article or research paper. The study described here provides evidence for the potential role of GPR4 antagonism in reducing inflammatory responses in synovial mast cells, suggesting its potential as a treatment strategy for rheumatoid arthritis.