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

Abstract

IL-1 signaling is mediated by the type I IL-1R (IL-1RI). The nonsignaling type II receptor has a regulatory function, since it reduces IL-1 effects by scavenging free IL-1 molecules. This regulatory function has been demonstrated only for the soluble form, released from the membrane receptor by action of specific proteases, but is still ill-defined for the membrane receptor itself. To assess the function of membrane IL-1RII, a modified IL-1RII cDNA was constructed, in which the cleavable domain was replaced with the corresponding uncleavable sequence of the epidermal growth factor receptor. The human keratinocyte line HaCaT, which does not express wild-type IL-1RII (wtIL-1RII), was stably transfected with this modified cDNA (unconventionally cleavable IL-1RII (uIL-1RII)). Cells transfected with uIL-1RII expressed the membrane form of IL-1RII, but were unable to produce the 60-kDa soluble receptor. Upon analysis of IL-1 responsiveness, parental HaCaT and vector-transfected cells (E27), expressing IL-1RI and the accessory chain IL-1R accessory protein, were responsive to IL-1. Conversely, cells overexpressing wtIL-1RII (811) or uIL-1RII (9D4) showed comparable reduction in responsiveness to both IL-1α (bound by membrane and soluble receptors) and IL-1β (recognized by the membrane receptor only), suggesting that the membrane form of the IL-1RII is mainly responsible for IL-1 inhibition. In contrast with wtIL-1RII, uIL-1RII did not interact with IL-1R accessory protein. Thus, the membrane form of IL-1RII possesses strong IL-1-inhibitory activity, independent of sequestration of the accessory protein and circumscribed to its ligand sink function.

IL-1β Scavenging by the Type II IL-1 Decoy Receptor in Human Neutrophils

“…It has recently been demonstrated that the membrane-bound form of IL-1RII is itself directly involved in the negative regulation of IL-1 (24) and that it acts as a dominant negative by forming a nonsignaling complex with the accessory protein (8,13,14). In the present study, we report that binding of IL-1 to membraneanchored IL-1RII causes internalization of the receptor-ligand complex, representing a further level of IL-1 autoregulation.…”

Transcriptional profiles during the differentiation and maturation of monocyte-derived dendritic cells, analyzed using focused microarrays

“…IL-1 (IL-1Α and IL-1Β), a multifunctional cytokine involved in a host of pro-inflammatory responses and diseases [50], affects target cells through two distinct types of transmembrane receptors, IL1R1 and IL1R2. IL1R1 transduces the signal from IL-1, while IL1R2 acts as a decoy receptor to subtract IL-1 from ILR1 [51,52]. The ratio between the expression of IL1R1 and IL1R2 has been shown to be the central factor in determining the responsiveness of a cell to IL-1 [53].…”

Anti-inflammatory functions of glucocorticoid-induced genes

“…The non-signaling type II IL-1 receptor (IL-1RII) is thought to function as a decoy receptor that inhibits cellular responses to IL-1 (Neumann et al, 2000). GC-induced upregulation of IL-1RII has been described in a number of studies (Brown et al, 1996;Colotta et al, 1993;Ehrchen et al, 2007;Pousset et al, 2001) and may contribute to inhibition of a very specific subset of (IL-1-mediated) inflammatory responses.…”