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*
Chrysalis, Princeton, NJ 08540;
Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110;
Bristol-Myers Squibb, Princeton, NJ 08543; and
§
Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877
The recently described IL-1R accessory protein (IL-1R AcP)
interacts with IL-1ß 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-
B 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-1
and
human IL-1R antagonist protein (IL-1Ra) with only moderately reduced
affinity when compared with wild-type cells, whereas murine IL-1ß
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-1ß. 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.
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