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.
Keywords: IL-1R1; IL-1β; SPR; oral fibroblasts; pro-inflammatory cytokines.