Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction

The interleukin-1 receptor antagonist (IL-lra) is a protein capable of inhibiting receptor binding and biological activities of IL-1 without inducing an IL-llike response.Equilibrium binding and kinetic experiments show that IL-lra binds to the 80-kDa IL-1 receptor on the murine thymoma cell line EL4 with an affinity (KO = 150 PM) approximately equal to that of IL-la and IL-18 for this receptor.However, IL-lra is unable to induce two early events associated with IL-1 activity.Surface-bound IL-lra does not undergo receptor-mediated internalization, and IL-Ira does not activate the protein kinase activity responsible for down-modulation of the EGF receptor on the murine 3T3 fibroblast cell line.The failure to induce general, early responses characteristic of IL-1 indicates that IL-lra is unlikely to act as an agonist on any cell expressing the 80-kDa receptor.IL-l'a and IL-18 bind with high affinity to cell-surface receptors found on numerous cell types (1, 2).This binding is a crucial first step in the induction of several aspects of inflammatory responses including leukocyte extravasation, protease production, and prostaglandin synthesis (3).Recently, we reported the purification and cloning of a third member of the IL-1 family which is an IL-1 receptor antagonist (IL-lra) (4-6).IL-Ira binds with high affinity to the 80- kDa IL-1 receptor found on T cells and fibroblasts and with somewhat lower affinity to the =67-kDa receptor on human neutrophils and B cells (4, 7).2,3In contrast to IL-la and IL-18, IL-lra elicits no detectable response on target cells and, in fact, can block the effects of either IL-la or IL-18 in a dose-dependent manner (4, 8-11).However, in view of the many activities of IL-1, it would be extremely difficult and perhaps impossible to prove that IL-lra lacks agonist activity in every conceivable IL-1 assay.Therefore, we chose to explore the effects of IL-lra on what are thought to be the initial, and presumably common steps of IL-1 action, on the assumption that a failure to detect agonist activity in these steps would indicate a general lack of such activity.One early event induced by IL-1 is the induction of a protein kinase activity that can phosphorylate specific substrates such