Downregulation of inflammatory cytokine release from IL-1β and LPS-stimulated PBMC orchestrated by ST2825, a MyD88 dimerisation inhibitor

• Type of Material: Article
• Authors: Sergio Ramírez-Pérez, Emory University; Luis Alexis Hernández-Palma, Universidad de Guadalajara; Edith Oregon-Romero, Universidad de Guadalajara; Brian Uriel Anaya-Macías, Universidad de Guadalajara; Samuel García-Arellano, Universidad de Guadalajara; Guillermo González-Estevez, Universidad de Guadalajara; José Francisco Muñoz-Valle, Universidad de Guadalajara
• Language: English
• Date: 2020-09-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/molecules25184322
• Title of Journal or Parent Work: Molecules
• Volume: 25
• Issue: 18
• Grant/Funding Information: This investigation was supported by funding from Universidad de Guadalajara-Fortalecimiento de la Investigación y el Posgrado 2018, Grant No. 244,159 assigned to José Francisco Muñoz-Valle.
• Keywords: Myeloid Differentiation Factor 88; Heterocyclic Compounds, 2-Ring; cytokine downregulation; Dose-Response Relationship, Drug; ST2825; MyD88 inhibition; Spiro Compounds; PBMC; Protein Structure, Quaternary; Anti-Inflammatory Agents; Leukocytes, Mononuclear; Interleukin-1beta; Humans; Protein Multimerization; Down-Regulation; Inflammation; Lipopolysaccharides
• Research Categories: Biology, Microbiology; Biology, Cell

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.