IL‐1F5 mediates anti‐inflammatory activity in the brain through induction of IL‐4 following interaction with SIGIRR/TIR8

Similarity in structure and sequence homology has led to the identification of new members of the interleukin‐1 (IL‐1) ligand and receptor superfamilies. IL‐1F6, IL‐1F8 and IL‐1F9 have been shown to signal through IL‐1R‐related protein 2 and IL‐1 receptor accessory protein leading to activation of NFκB, while IL‐1F7 and IL‐1F10 interact with the IL‐18 receptor and the soluble IL‐1 receptor type I respectively. In contrast, identification of a biological role for IL‐1F5 has remained elusive, with conflicting data relating to its possible ability to antagonize IL‐1F9‐stimulated activation of NFκB in Jurkat cells transfected with IL‐1R‐related protein 2. In this study, we set out to investigate a possible role for IL‐1F5 in the brain and report that it antagonizes the inflammatory effects of IL‐1β and lipopolysaccharide (LPS) in vivo and in vitro including the inhibitory effect on long‐term potentiation (LTP) in rat hippocampus. We demonstrate that IL‐1F5 induces IL‐4 mRNA and protein expression in glia in vitro and enhances hippocampal expression of IL‐4 following intracerebroventricular (i.c.v.) injection. The inhibitory effect of IL‐1F5 on LPS‐induced IL‐1β is attenuated in cells from IL‐4‐defective (IL−4 −/− mice). Our findings suggest that IL‐1F5 mediates anti‐inflammatory effects through its ability to induce IL‐4 production and that this is a consequence of its interaction with the orphan receptor, single Ig IL‐1R‐related molecule (SIGIRR)/TIR8, as the effects were not observed in SIGIRR −/− mice. In contrast to its effects in brain tissue, IL‐1F5 did not attenuate LPS‐induced changes, or up‐regulated IL‐4 in macrophages or dendritic cells, suggesting that the effect is confined to the brain.