The type II IL-1 receptor interacts with the IL-1 receptor accessory protein: a novel mechanism of regulation of IL-1 responsiveness.
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.
Lang
D
D
Molekularpharmakologie, Medizinische Hochschule Hannover, Germany.
Knop
J
J
Wesche
H
H
Raffetseder
U
U
Kurrle
R
R
Boraschi
D
D
Martin
M U
MU
D000818:Animals; D001667:Binding, Competitive; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D053577:Interleukin-1 Receptor Accessory Protein; D007376:Interleukin-2 / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000473:pathology; D046911:Macromolecular Substances; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I; D053574:Receptors, Interleukin-1 Type II; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured
C507765:IL1RAP protein, human; C507767:Il1rap protein, mouse; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D007376:Interleukin-2; D046911:Macromolecular Substances; D011506:Proteins; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D053574:Receptors, Interleukin-1 Type II; D011993:Recombinant Fusion Proteins