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
NFkappaB, 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
NFkappaB 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-1beta 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-1beta 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.
