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 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.
Costelloe
Ceire
C
Trinity College Institute for Neuroscience, Trinity College, Dublin, Ireland.
Watson
Melanie
M
Murphy
Aine
A
McQuillan
Keith
K
Loscher
Christine
C
Armstrong
Michelle E
ME
Garlanda
Cecilia
C
Mantovani
Alberto
A
O'Neill
Luke A J
LA
Mills
Kingston H G
KH
Lynch
Marina A
MA
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D018836:Inflammation Mediators / Q000502:physiology*; D007375:Interleukin-1 / Q000378:metabolism / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C478197:Il36rn protein, mouse; D018836:Inflammation Mediators; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse; D015847:Interleukin-4