IL-1 beta scavenging by the type II IL-1 decoy receptor in human neutrophils.
IL-1 elicits its cellular effects by binding a heterodimeric receptor consisting of IL-1RI and the accessory protein, IL-1RAcPr. In addition, it binds to IL-1RII, which lacking signaling function has been ascribed a decoy role. The fate of the ligand following interaction with the decoy receptor was examined in human polymorphonuclear cells (PMN), which express predominantly (>90%) IL-1RII. Incubation of PMN with IL-1beta results in a rapid decrease in cell surface-associated ligand accompanied by a concomitant increase in internalized IL-1 with 50-60% of IL-1beta located intracellularly within 1 h at 37 degrees C. The use of blocking Abs revealed that IL-1 internalization is mediated exclusively by the decoy receptor. The results of inhibitor analysis demonstrate that internalization requires ATP synthesis and involves clathrin-mediated endocytosis. Following removal of the ligand, the receptor was rapidly re-expressed on the cell surface. Cyclohexamide, a protein synthesis inhibitor, had no effect upon the process, suggesting that the re-expressed receptor was recycled. In addition, human keratinocytes stably transfected with IL-1RII (HaCAT 811) also internalized the IL-1RII with 43% cell surface receptor internalized after 90 min. Immunofluorescence microscopy revealed colocalization of the internalized receptor with wheat germ agglutinin-labeled internalized glycoproteins and early endosome Ag-1, a protein associated with the early endosome compartments, indicative of cellular uptake of IL-1RII by endocytosis. In contrast, little or no internalization was observed in other cells of immune origin. These results suggest that the decoy receptor IL-1RII can act as a scavenger of IL-1, representing a novel autoregulatory mechanism of the IL-1 system.
Bourke
Emer
E
Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy.
Cassetti
Arianna
A
Villa
Antonello
A
Fadlon
Emma
E
Colotta
Francesco
F
Mantovani
Alberto
A
D001152:Arsenicals / Q000494:pharmacology; D001324:Autoantigens / Q000378:metabolism; D002103:Cadaverine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D002966:Clathrin / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D053574:Receptors, Interleukin-1 Type II; D019810:Sodium Azide / Q000494:pharmacology; D013997:Time Factors; D033921:Vesicular Transport Proteins
D001152:Arsenicals; D001324:Autoantigens; D002966:Clathrin; D007375:Interleukin-1; D007457:Iodine Radioisotopes; D008024:Ligands; D008565:Membrane Proteins; D017472:Receptors, Interleukin-1; D053574:Receptors, Interleukin-1 Type II; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; C029341:oxophenylarsine; D019810:Sodium Azide; C008542:monodansylcadaverine; D002103:Cadaverine