IL-1 receptor accessory protein is an essential component of the IL-1 receptor.
The recently described IL-1R accessory protein (IL-1R AcP) interacts with IL-1beta and the IL-1 type-IR (IL-1RI), but an essential requirement for IL-1R AcP in IL-1 signaling in vitro has not been established and its role in vivo has not been examined. In this study, IL-1R AcP-deficient mice and fibroblasts were produced and characterized. All IL-1 agonists bound to IL-1R AcP-deficient cells through the type I IL-1R, but failed to activate gene expression through either the nuclear factor-kappaB or AP-1-dependent signaling pathways. Absence of IL-1R AcP differentially affected the affinity for IL-1 ligands. IL-1R AcP-deficient fibroblasts bound murine IL-1alpha and human IL-1R antagonist protein (IL-1Ra) with only moderately reduced affinity when compared with wild-type cells, whereas murine IL-1beta affinity was reduced by 70-fold. IL-1 also failed to produce a biologic response in vivo in IL-1R AcP-deficient mice. These data demonstrate that a type I IL-1R/IL-1R AcP complex is required for signaling by all IL-1 agonists and for high affinity binding by IL-1beta. Finally, IL-1R AcP is an essential signal transducing component of the functional IL-1R and should represent a novel target for blocking IL-1 function in human disease.
Cullinan
E B
EB
Chrysalis, Princeton, NJ 08540, USA.
Kwee
L
L
Nunes
P
P
Shuster
D J
DJ
Ju
G
G
McIntyre
K W
KW
Chizzonite
R A
RA
Labow
M A
MA
D000818:Animals; D001667:Binding, Competitive / Q000276:immunology; D002460:Cell Line; D004622:Embryo, Mammalian; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D018390:Gene Targeting; D007375:Interleukin-1 / Q000494:pharmacology; D053577:Interleukin-1 Receptor Accessory Protein; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C507765:IL1RAP protein, human; C507767:Il1rap protein, mouse; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D015850:Interleukin-6; D011506:Proteins; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha