Anti-inflammatory effects of Single-Ig Interleukin-1 (IL-1)-related receptor (SIGIRR) in the brain : interaction with IL-1F5

Abstract

It is well established that inflammatory changes in the brain are associated with ageing and neurodegenerative disorders. Central to these changes is activation of microglial cells with the accompanying increases in the pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) and activation of downstream signalling cascades. The IL-1 ligand and receptor super-family have been shown to play pivotal roles in CNS-mediated inflammation. However, recent data show that single-lg IL-1-related receptor (SIGIRR), an orphan receptor, is structurally and functionally different from the other members and is a negative regulator of Toll-like receptor/IL-1 receptor (TLR/IL-IR) signalling. The ligand and downstream signalling events induced by SIGIRR are largely unknown. Interestingly, a newly characterised member of the IL-1 ligand super-family, termed interleukin-1F5 (1L-1F5), which shares significant homology with IL-1 receptor antagonist (IL-1ra) and exhibits anti-inflammatory actions, does not bind to any of the IL-1Rs suggesting it may be a ligand for an orphan receptor. The aims of this study were to characterise the expression of SIGIRR in the brain, investigate the anti-inflammatory actions of SIGIRR and IL-1F5 on lipopolysaccharide (LPS), amyloid-β (Aβ) and age-associated inflammatory changes, and to establish if the anti-inflammatory effects of IL-1 F5 are dependent on its interaction with SIGIRR.