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.
Two IL-1 receptors have been identified, termed type I and type II. The extracellular domain of the type II IL-1 receptor is released from certain cells and can function as a specific inhibitor of IL-1 beta activity. We assessed the ligand-binding properties of the type II membrane-bound and soluble IL-1 receptor (sIL-1R) from the human B cell line Raji by competition. Upon release, the affinity of sIL-1R for IL-1 alpha and IL-1 beta remained constant, and both soluble and cell surface IL-1 receptors bound to the same regions on the IL-1 beta molecule as defined by binding of a series of IL-1 beta mutant molecules. However, the affinity of sIL-1R for the IL-1 receptor antagonist (IL-1ra) decreased by a factor of 2000 when compared with the cell surface receptor. Type II sIL-1R and IL-1ra had an additive effect in inhibiting the binding of IL-1 beta to cell surface IL-1 receptors. In contrast, the combination of recombinant type 1 sIL-1R with IL-1ra abrogated the inhibition seen with each of the individual agents alone. The type II cell surface IL-1 receptor failed to bind the biologically inactive IL-1 beta precursor molecule, but binding to the IL-1 beta precursor was observed on cellular release of the receptor; this was confirmed with 35S-labeled IL-1 beta. Binding of IL-1 beta precursor by sIL-1R inhibited the precursor's ability to be processed to the mature, biologically active 17-kDa species. These observations suggest that the type II sIL-1R inhibits IL-1 beta at two steps, by preventing processing of propeptide and by blocking the interaction of mature IL-1 beta with type I IL-1 receptor. In addition, type II sIL-1R does not interfere with inhibition mediated by IL-1ra.
Symons
J A
JA
Department of Medicine, University of Sheffield, Royal Hallamshire Hospital, United Kingdom.
Young
P R
PR
Duff
G W
GW
D006801:Humans; D066298:In Vitro Techniques; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism*; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D011498:Protein Precursors; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins