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 fib...

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Bibliographic Details
Published in:The Journal of immunology (1950) 1998-11, Vol.161 (10), p.5614-5620
Main Authors: Cullinan, Emily B, Kwee, Lia, Nunes, Perla, Shuster, David J, Ju, Grace, McIntyre, Kim W, Chizzonite, Richard A, Labow, Mark A
Format: Article
Language:English
Subjects:
Animals
Binding, Competitive - immunology
Cell Line
Embryo, Mammalian
Female
Fibroblasts - metabolism
Gene Expression Regulation - immunology
Gene Targeting
Interleukin-1 - pharmacology
Interleukin-1 Receptor Accessory Protein
Interleukin-6 - biosynthesis
Male
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Proteins - genetics
Proteins - physiology
Receptors, Interleukin-1 - genetics
Receptors, Interleukin-1 - physiology
Stem Cells
Tumor Necrosis Factor-alpha - pharmacology
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.161.10.5614