Soluble type II interleukin 1 (IL-1) receptor binds and blocks processing of IL-1 beta precursor and loses affinity for IL-1 receptor antagonist.

Abstract

The human IL-1 gene family comprises IL-la, IL-1f3, and IL-1 receptor antagonist (IL-lra). All three share limited amino acid identity and bind to the same receptors on different cell types (1). In the case of IL-ia and IL-11, ligand-receptor interaction activates signaling pathways involved in both immune and inflammatory responses. Binding of IL-lra to the IL-1 receptor (IL-lR) does not trigger signal transduction, and the actions of IL-la and IL-113 are blocked by this unique antagonist protein (2).Both IL-ia and IL-1,B are initially synthesized as precursor proteins of 31 kDa and are processed to 17-kDa mature polypeptides upon release. However, release does not seem to be dependent on processing, as significant amounts of IL-1 precursor can be found in the extracellular medium (3). The

The Membrane Form of the Type II IL-1 Receptor Accounts for Inhibitory Function

“…This observation emphasizes the notion that membrane IL-1RII can act as a ligand sink, whereas on the other hand it sheds some light on the conformational requirements for an effective interaction between IL-1RII and IL-1RAcP. Results from earlier studies show that wtIL-1RII in its membrane form can bind IL-1␣ and IL-1␤, but not the 31-kDa precursor form of IL-1␤ (17). Once released from the surface by proteolytic cleavage, the ligand-binding characteristics of IL-1RII change dramatically.…”

“…To date, the IL-1-inhibitory function of the IL-1RII has been clearly demonstrated for the soluble form (17,22,32) and in systems in which both membrane and sIL-1RII were present (22,33,34). It still remains a matter of investigation whether the functional role of membrane IL-1RII is only that being a source for soluble inhibitory receptor or whether membrane IL-1RII itself contributes to the negative regulation of IL-1 activity by acting as ligand sink, as suggested by indirect data (12,29).…”

“…sIL-1RII molecules are found in cell culture supernatants (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) and in biological fluids under several physiopathological conditions (13,(25)(26)(27)(28)(29). Although it has been reported that the soluble receptor could be generated by an alternatively spliced IL-1RII mRNA (30), sIL-1RII is mainly produced by cleavage of the IL-1RII extracellular domain by a so far unidentified metalloproteinase (31).…”

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

“…However, this does not lead to signal transduction because this receptor lacks the intracellular Toll-IL-1 receptor domain that is crucial for MyD88 binding (16)(17)(18). Therefore, the type II receptor is a decoy receptor as has been described for its transmembrane and soluble forms (19).…”

“…It is generally accepted that occupation of only 1% of the IL-1RI by IL-1 instigates full-blown cell activation, and as a consequence, relatively high amounts of IL-1Ra (100-1,000-fold molar excess) are required to fully block IL-1. Fortunately, IL-1Ra binds poorly to IL-1RII (19), and both IL-1Ra and soluble IL-1RII (sIL-1RII) cooperate in IL-1 inhibition. We have demonstrated that administration of IL-1Ra protein or the IL-1Ra gene ameliorates disease in several models of experimental arthritis, with a profound protective effect against cartilage and bone destruction (20,21).…”