A central nervous system-restricted isoform of the interleukin-1 receptor accessory protein modulates neuronal responses to interleukin-1.
Interleukin-1 (IL-1) has multiple functions in both the periphery and the central nervous system (CNS) and is regulated at many levels. We identified an isoform of the IL-1 receptor (IL-1R) accessory protein (termed AcPb) that is expressed exclusively in the CNS. AcPb interacted with IL-1 and the IL-1R but was unable to mediate canonical IL-1 responses. AcPb expression, however, modulated neuronal gene expression in response to IL-1 treatment in vitro. Animals lacking AcPb demonstrated an intact peripheral IL-1 response and developed experimental autoimmune encephalomyelitis (EAE) similarly to wild-type mice. AcPb-deficient mice were instead more vulnerable to local inflammatory challenge in the CNS and suffered enhanced neuronal degeneration as compared to AcP-deficient or wild-type mice. These findings implicate AcPb as an additional component of the highly regulated IL-1 system and suggest that it may play a role in modulating CNS responses to IL-1 and the interplay between inflammation and neuronal survival.
Smith
Dirk E
DE
Department of Inflammation Research, Amgen, Seattle, WA 98119, USA. smithde@amgen.com
Lipsky
Brian P
BP
Russell
Chris
C
Ketchem
Randal R
RR
Kirchner
Jacqueline
J
Hensley
Kelly
K
Huang
Yangyang
Y
Friedman
Wilma J
WJ
Boissonneault
Vincent
V
Plante
Marie-Michèle
MM
Rivest
Serge
S
Sims
John E
JE
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001253:Astrocytes / Q000276:immunology; D001483:Base Sequence; D001921:Brain / Q000166:cytology / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007375:Interleukin-1 / Q000378:metabolism*; D053577:Interleukin-1 Receptor Accessory Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009474:Neurons / Q000276:immunology*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D016207:Cytokines; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D020033:Protein Isoforms