DPIE [2-(1,2-diphenyl-1H-indol-3-yl)ethanamine] Augments Pro-Inflammatory Cytokine Production in IL-1β-Stimulated Primary Human Oral Cells

• Published in: International journal of molecular sciences 2018-06, Vol.19 (7), p.1835
• Main Authors: Ahn, Sun-Hee, Lee, Jin-Kyung, Kim, Nam Doo, Kim, Seok-Ho, Lee, Sunwoo, Jung, Seunggon, Chay, Kee-Oh, Lee, Tae-Hoon
• Format: Article
• Language: English
• Subjects: Amines - chemistry; Amines - pharmacology; Autoimmune diseases; Binding; Cell Survival - drug effects; Cells, Cultured; Computer applications; Cyclooxygenase-2; Cytokines; Cytokines - metabolism; Cytotoxicity; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Gingiva - cytology; Humans; IL-1R1; IL-1β; Inflammation; Inflammation Mediators - metabolism; Interleukin 1; Interleukin 1 receptors; Interleukin 6; Interleukin 8; Interleukin-1beta - pharmacology; Molecular Structure; mRNA; oral fibroblasts; Periodontal ligament; Periodontal Ligament - cytology; Periodontal Ligament - drug effects; Periodontal Ligament - metabolism; pro-inflammatory cytokines; Protein Binding - drug effects; Proteins; Receptors, Interleukin-1 Type I - metabolism; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; SPR; Surface Plasmon Resonance
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19071835

Interleukin-1β (IL-1β) is a prominent pro-inflammatory cytokine that is implicated in a variety of autoimmune diseases and plays an important role in host defense against infections. IL-1β activity increases with its increasing binding capacity to IL-1 receptors (IL-1Rs). Thus, numerous studies have targeted the discovery of molecules modulating the interactions between IL-1β and IL-1R1. We have conducted an IL-1R1 structure-based virtual screening to identify small molecules that could alter IL-1β activity, using in silico computational analysis. Sixty compounds from commercial libraries were predicted to bind to IL-1R1, and their influence on cytokine production in IL-1β-stimulated gingival fibroblasts (GFs) was determined. Of these, only (2-(1,2-diphenyl-1H-indol-3-yl)ethanamine (DPIE) showed a synergistic increase in inflammatory molecules and cytokine production (IL-6, IL-8, and COX-2) at both mRNA and protein levels in IL-1β-stimulated GFs. The enhancing activity of DPIE in IL-1β-induced cytokine production increased in a dose-dependent manner without cytotoxicity. This pattern was also observed in IL-1β-stimulated primary human periodontal ligament cells (PDLs). Furthermore, we measured the impact of DPIE on the IL-1β⁻IL-1R1 system using surface plasmon resonance and demonstrated that DPIE increased the binding affinity of IL-1β to IL-1R1. These data indicate that DPIE boosts IL-1β signaling by enhancing the binding of IL-1β to IL-1R1 in oral primary cells.