title: 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.
abstract: 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.
authors.affiliation: Research Center Dompé S.p.A., L'Aquila, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Ruggiero
authors.forename: P
authors.initials: P
authors.lastname: Bossù
authors.forename: G
authors.initials: G
authors.lastname: Macchia
authors.forename: E
authors.initials: E
authors.lastname: Del Grosso
authors.forename: V
authors.initials: V
authors.lastname: Sabbatini
authors.forename: R
authors.initials: R
authors.lastname: Bertini
authors.forename: A
authors.initials: A
authors.lastname: Colagrande
authors.forename: C
authors.initials: C
authors.lastname: Bizzarri
authors.forename: G
authors.initials: G
authors.lastname: Maurizi
authors.forename: V
authors.initials: V
authors.lastname: Di Cioccio
authors.forename: G
authors.initials: G
authors.lastname: D'Andrea
authors.forename: A
authors.initials: A
authors.lastname: Di Giulio
authors.forename: F
authors.initials: F
authors.lastname: Frigerio
authors.forename: R
authors.initials: R
authors.lastname: Grifantini
authors.forename: G
authors.initials: G
authors.lastname: Grandi
authors.forename: A
authors.initials: A
authors.lastname: Tagliabue
authors.forename: D
authors.initials: D
authors.lastname: Boraschi
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D011485:Protein Binding; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins