Abstract
BackgroundInterleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide.MethodsWe investigated the binding of Ilantide to IL-1 receptor type I (IL-1RI) using surface plasmon resonance, the inhibition of Il-1β-induced activation of nuclear factor κB (NF-κB) in HEK-Blue cells that contained an IL-1β-sensitive reporter, the secretion of TNF-α in macrophages, protection against IL-1-induced apoptosis in neonatal pancreatic islets, and the penetration of Ilantide through the blood–brain barrier using competitive enzyme-linked immunosorbent assay (ELISA). We studied the effects of the peptide on social behavior and memory in rat models of lipopolysaccharide (LPS)- and amyloid-induced neuroinflammation, respectively, and its effect in a rat model of experimental autoimmune enchephalomyelitis.ResultsIlantide bound IL-1RI, inhibited the IL-1β-induced activation of NF-κB, and inhibited the secretion of TNF-α in vitro. Ilantide protected pancreatic islets from apoptosis in vitro and reduced inflammation in an animal model of arthritis. The peptide penetrated the blood–brain barrier. It reduced the deficits in social activity and memory in LPS- and amyloid-treated animals and delayed the development of experimental autoimmune enchephalomyelitis.ConclusionsThese findings indicate that Ilantide is a novel and potent IL-1RI antagonist that is able to reduce inflammatory damage in the central nervous system and pancreatic islets.
Highlights
Interleukin 1 (IL-1) is a key mediator of the acute-phase inflammatory response and has been implicated as the mediator of tissue dysfunction and destruction in chronic inflammatory diseases such as amyotrophic lateral sclerosis, diabetes and rheumatoid arthritis
A peptide modeled after the IL-1 receptor antagonist (IL-1Ra) binding site for IL-1 receptor type I (IL-1RI), binds to the ectodomain of IL-1RI with an affinity comparable to the cytokine Using a model of the tertiary structure of the IL-1Ra– IL-1RI complex [PDB:1IRA] [19], we designed a peptide ten amino acids long from the N terminus of IL-1Ra, termed Ilantide (IL-1 antagonistic peptide), a part of the IL-1Ra protein that interacts with the Ig3 module of the type I receptor (Figure 1)
We studied the binding of the peptide to IL-1RI by surface plasmon resonance (SPR) analysis
Summary
Interleukin 1 (IL-1) is a key mediator of the acute-phase inflammatory response and has been implicated as the mediator of tissue dysfunction and destruction in chronic inflammatory diseases such as amyotrophic lateral sclerosis, diabetes and rheumatoid arthritis. IL-1 signals via IL-1 receptor type I (IL-1RI), which binds both the IL-1α and IL-1β isoforms [2]. Ana has been used for the treatment of rheumatoid arthritis, adult-onset Still’s disease, systemic onset juvenile idiopathic arthritis, osteoarthritis and type 2 diabetes mellitus [5,6]. The relatively poor penetration of the blood–brain barrier (BBB) [7] restricts therapeutic use of the current macromolecular IL-1 antagonist proteins for the treatment of neuroinflammation [8]. Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide
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