The Type II IL-1 Receptor Interacts with the IL-1 Receptor Accessory Protein: A Novel Mechanism of Regulation of IL-1 Responsiveness

• Published in: The Journal of immunology (1950) Vol. 161; no. 12; pp. 6871 - 6877
• Main Authors: Lang, Detlef, Knop, Johannes, Wesche, Holger, Raffetseder, Ute, Kurrle, Roland, Boraschi, Diana, Martin, Michael U
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.12.1998
• Subjects: Animals; Binding, Competitive; Humans; Interleukin-1 - pharmacology; Interleukin-1 - physiology; Interleukin-1 Receptor Accessory Protein; Interleukin-2 - secretion; Lymphoma, T-Cell - pathology; Macromolecular Substances; Mice; Models, Biological; Protein Binding; Protein Structure, Tertiary; Proteins - metabolism; Receptors, Interleukin-1 - chemistry; Receptors, Interleukin-1 - genetics; Receptors, Interleukin-1 - metabolism; Receptors, Interleukin-1 Type I; Receptors, Interleukin-1 Type II; Recombinant Fusion Proteins - physiology; Signal Transduction; Structure-Activity Relationship; Transfection; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.161.12.6871

IL-1 binds to two types of receptors on the cell membrane, of which only type I (IL-1RI) transduces signals in concert with the coreceptor IL-1 receptor accessory protein (IL-1RAcP) while type II (IL-1RII) allegedly functions solely as ligand sink and decoy receptor without participating in IL-1 signaling. To investigate the regulatory role of IL-1RII on IL-1 responsiveness, a chimeric receptor encompassing the extracellular and transmembrane portions of IL-1RII and the cytoplasmic signal-transducing domain of IL-1RI was transfected into two murine EL-4-derived sublines that do or do not express IL-1RAcP, respectively. The chimeric receptor was able to transduce the IL-1 signal and induce IL-2 production only in the cell line which expressed IL-1RAcP, suggesting effective interaction between the extracellular domains of IL-1RII and IL-1RAcP in the presence of IL-1. The physical association of ligated IL-1RII with IL-1RAcP was proven by crosslinking experiments with radio-iodinated IL-1 and subsequent immunoprecipitations in normal human B cells and in EL-4 D6/76 cells transiently cotransfected with IL-1RII and IL-1RAcP, respectively. Based on these findings, it is proposed that upon IL-1 binding IL-1RII can recruit IL-1RAcP into a nonfunctional trimeric complex and thus modulate IL-1 signaling by subtracting the coreceptor molecule from the signaling IL-1RI. In this novel mechanism of coreceptor competition, the ratio between IL-1RII and IL-1RI becomes the central factor in determining the IL-1 responsiveness of a cell and the availability of IL-1RAcP becomes limiting for effective IL-1 signaling.