A Single Amino Acid Difference between Human and Monkey Interleukin (IL)-1β Dictates Effective Binding to Soluble Type II IL-1 Receptor*

Soluble type II interleukin (IL)-1 receptor (sIL1R-II) binds human IL-1β with high affinity and neutralizes its activity. Recombinant sIL1R-II is considered a potentially useful anti-IL-1 therapeutic, and preclinical studies have been undertaken with this molecule in primates. To better understand the cytokine-receptor interactions occurring in this nonhuman context, monkey IL-1 and IL1R-II were cloned, and their binding abilities were examined in vitro. IL-1β from cynomolgus monkey was capable of binding and activating the human type I IL-1 receptor. However, unlike human IL-1β, it was unable to effectively bind and become neutralized by sIL1R-II. Human and cynomolgus IL-1β proteins are 96% identical, differing by only six amino acids. Structural and mutational analysis revealed that the unique sIL1R-II binding ability of human IL-1β is due to a single amino acid difference compared with monkey IL-1β.

[1]  A. Morris,et al.  Expression Augmenting Sequence Element (EASE) Isolated From Chinese Hamster Ovary Cells , 1997 .

[2]  R. Raag,et al.  Functional implications of interleukin‐1β based on the three‐dimensional structure , 1992 .

[3]  Ronald W. Barrett,et al.  A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist , 1997, Nature.

[4]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[5]  B. Brandhuber,et al.  Crystal structure of the type-I interleukin-1 receptor complexed with interleukin-1β , 1997, Nature.

[6]  M Locati,et al.  Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines. , 2001, Trends in immunology.

[7]  A. Mantovani,et al.  The type II 'decoy' receptor: a novel regulatory pathway for interleukin 1. , 1994, Immunology today.

[8]  A. Bowie,et al.  The Interleukin-1 Receptor/toll-like Receptor Superfamily: Signal Generators for Pro-inflammatory Interleukins and Microbial Products , 2022 .

[9]  William Clevenger,et al.  Cloning and Characterization of an Alternatively Processed Human Type II Interleukin-1 Receptor mRNA* , 1996, The Journal of Biological Chemistry.

[10]  A. Mantovani,et al.  The type II decoy receptor of IL‐1 inhibits murine collagen‐induced arthritis , 2000, European journal of immunology.

[11]  C. Dinarello,et al.  Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. , 1998, International reviews of immunology.

[12]  R. Dubose,et al.  Identification and cloning of a novel IL‐15 binding protein that is structurally related to the alpha chain of the IL‐2 receptor. , 1995, The EMBO journal.

[13]  G L Gilliland,et al.  Combining experimental information from crystal and solution studies: joint X-ray and NMR refinement. , 1992, Science.

[14]  A. Schmitz,et al.  A mutational analysis of receptor binding sites of interleukin-1β:differences in binding of human interleukin-1β muteins to human and mouse receptors , 1994 .

[15]  A. Goldman,et al.  Structure of an interleukin-1 beta mutant with reduced bioactivity shows multiple subtle changes in conformation that affect protein-protein recognition. , 1993, Biochemistry.

[16]  A. Sali,et al.  Comparative protein structure modeling of genes and genomes. , 2000, Annual review of biophysics and biomolecular structure.

[17]  M. Meseck,et al.  Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation1 , 2002, The Journal of Immunology.

[18]  J. Bray,et al.  Mapping receptor binding sites in interleukin (IL)-1 receptor antagonist and IL-1 beta by site-directed mutagenesis. Identification of a single site in IL-1ra and two sites in IL-1 beta , 1995, The Journal of Biological Chemistry.

[19]  M. Gayle,et al.  Interleukin 1 signaling occurs exclusively via the type I receptor. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Labow,et al.  Molecular Cloning and Characterization of a Second Subunit of the Interleukin 1 Receptor Complex (*) , 1995, The Journal of Biological Chemistry.

[21]  M. Carrondo,et al.  Animal Cell Technology , 1997, Springer Netherlands.

[22]  S. Matsufuji,et al.  Antiproliferative effect of IL-1 is mediated by p38 mitogen-activated protein kinase in human melanoma cell A375. , 1999, Journal of immunology.

[23]  P. Auron,et al.  The interleukin 1 receptor: ligand interactions and signal transduction. , 1998, Cytokine & growth factor reviews.

[24]  F. Villinger,et al.  Comparative sequence analysis of cytokine genes from human and nonhuman primates. , 1995, Journal of immunology.