Inhibitory activity of IL-1 receptor antagonist depends on the balance between binding capacity for IL-1 receptor type 1 and IL-1 receptor type II

• Published in: The Journal of immunology (1950) Vol. 158; no. 8; pp. 3881 - 3887
• Main Authors: Ruggiero, P, Bossu, P, Macchia, G, Del Grosso, E, Sabbatini, V, Bertini, R, Colagrande, A, Bizzarri, C, Maurizi, G, Di Cioccio, V, D'Andrea, G, Di Giulio, A, Frigerio, F, Grifantini, R, Grandi, G, Tagliabue, A, Boraschi, D
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.04.1997
• Subjects: Animals; Cell Line; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Mice; Mice, Inbred C3H; Mutation; Protein Binding; Receptors, Interleukin-1 - antagonists & inhibitors; Receptors, Interleukin-1 - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Sialoglycoproteins - genetics; Sialoglycoproteins - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.158.8.3881

A series of mutants of human IL-1 receptor antagonist (IL-1ra) has been designed by comparison of IL-1ra and IL-1beta structures in order to increase receptor antagonist capacity. Upon in vitro and in vivo assay of IL-1 antagonism, the IL-1ra mutants DoB 0039 (N91-->R), DoB 0040 (T109-->A) and DoB 0041 (N91/T109-->R/A) could inhibit IL-1beta effects more efficiently than wild-type IL-1ra, with DoB 0041 being the most active. Analysis of the receptor-binding capacity of the IL-1ra mutants showed that all three mutants could inhibit binding of IL-1alpha or IL-1beta to IL-1RI-bearing cells more efficiently than wild-type IL-1ra. Conversely, binding of IL-1beta to IL-1RII-bearing cells could be inhibited by DoB 0041 much less efficiently than by wild-type IL-1ra. It is known that the two types of IL-1 receptors (IL-1RI and IL-1RII) play different roles in the regulation of IL-1 activity, with IL-1RI being solely responsible for cell triggering upon IL-1 binding, whereas IL-1RII acts as a scavenger of IL-1 and can thus be considered as a natural IL-1 inhibitor. Thus, the enhanced inhibitory capacity of DoB 0041 as compared with wild-type IL-1ra is explained in terms of better binding to the activating receptor IL-1RI and poorer interaction with the inhibitory receptor IL-1RII.