Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor

Abstract

The inflammatory process implicates homeostasis disruption and increased production of inflammatory mediators. Myeloid differentiation primary response 88 (MyD88) is an essential protein recruited after lipopolysaccharide (LPS) and interleukin (IL)-1β stimulation, a process that converges in nuclear factor kappa B (NF-κB) activation, as well as a transcription of several genes of both pro- and anti-inflammatory cytokines. The inhibition of MyD88 has shown efficacy by decrease inflammatory response, and has demonstrated potential application as a therapeutic target in chronic diseases. In this study, we investigate the effect of MyD88 dimerisation inhibitor ST2825 on cytokine production from rhIL-1β and LPS-stimulated peripheral blood mononuclear cells (PBMC) from healthy blood donors (HBD). ST2825 significantly downregulates the production of IFN-γ, IL-6, IL-12, IL-2, IL-15, IL-7, VEGF, IL-1Ra, IL-4, IL-5, IL-13 and IL-9 (p < 0.05) in LPS-stimulated PBMC. Moreover, ST2825 had a relatively low impact on IL-1β signalling pathway inhibition, showing that only a few specific cytokines, such as IFN-γ and IL-1Ra, are inhibited in rhIL-1β-stimulated PBMC (p < 0.01). In conclusion, MyD88 dimerisation inhibitor ST2825 showed high efficacy by inhibiting pro- and anti-inflammatory cytokine production in LPS-stimulated PBMC. Moreover, although rhIL-1β induced a sustained cytokine production (p < 0.05), ST2825 did not show a significant effect in the secretion of neither pro- nor anti-inflammatory cytokines in rhIL-1β-stimulated PBMC.

Limonin Inhibits IL-1β-Induced Inflammation and Catabolism in Chondrocytes and Ameliorates Osteoarthritis by Activating Nrf2

“…Furthermore, we also investigated whether limonin alleviates osteoarthritis in mice through any other pathways. Previous studies have reported that IL-1 β can activate Myd88 [ 39 , 40 ]. Myd88 is the most critical effector molecule in the signal transduction of TLRs.…”

Role of Adaptor Protein Myeloid Differentiation 88 (MyD88) in Post-Subarachnoid Hemorrhage Inflammation: A Systematic Review

“…More specifically, these bind with the BB-loop of the TIR domain on MyD88, hence, thwarting MyD88 homo-dimerization. This is associated with the abrogation of the signaling involving MyD88, TIRAP and TLR4, and therefore, myddosome formation [60,61].…”

Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naïve Rheumatoid Arthritis Patients

“…In addition, the Aryl hydrocarbon receptor, known as Th17 cell differentiation promoter ( Nakahama et al, 2011 ; Talbot et al, 2018 ), and TREM1 signalling involved in systemic and local inflammatory process activation ( Kuai et al, 2009 ; Peng et al, 2019 ; Inanc et al, 2021 ), were also processes identified to be associated with the DMARDs-naïve RA PBMC. Based on our previous findings of the role of ST2825 in downregulating the release of proinflammatory cytokines in PBMC from healthy subjects ( Ramírez-Pérez et al, 2020 ); we tested whether this chemical compound could modulate gene expression signatures and canonical pathways on PBMC from RA patients. Our findings indicate that ST2825 downregulates an enormous number of genes that are increased in RA patients compared with healthy subjects.…”

“…The MyD88 inhibitor ST2825 was added to the corresponding well 30 min before stimulation with LPS or rhIL-1β. A treatment concentration of 30 μM ST2825 was chosen based on our previous study in healthy PBMC ( Ramírez-Pérez et al, 2020 ). Experiments were done in duplicates, and PBMC were incubated for 24 h at 37°C in a humidified 5% CO 2 atmosphere.…”

“…Targeting MyD88 by the effect of the synthetic chemical compound ST2825 has shown a significant decrease in the production of proinflammatory cytokines such as IL-1β, IL-6, TNF-α and IL-12 after LPS stimulation in macrophages ( Long et al, 2018 ), kidney epithelial cells ( Qi et al, 2016 ) and PBMC from healthy subjects ( Ramírez-Pérez et al, 2020 ). The precise ST2825 mechanism-of-action for inhibiting MyD88 is mediated by interfering with homo-oligomerization of BB loop in the MyD88 TIR domain and thereby affecting its dimerization and downstream signalling activation ( Loiarro et al, 2007 ; Loiarro et al, 2013 ; Chen et al, 2020 ).…”