Targeting interleukin 18 with interleukin 18 binding protein

Area of Science:

• Immunology
• Protein biochemistry

Background:

• Interleukin 18 (IL18) is a key inducer of interferon gamma (IFNγ), crucial for T-helper type 1 immune responses.
• A novel, secreted protein, IL18 binding protein (IL18BP), has been identified that neutralizes IL18.
• IL18BP shares characteristics with soluble IL1 family receptors but lacks a transmembrane domain, indicating it is secreted rather than cell-surface anchored.

Purpose of the Study:

• To characterize the novel IL18 binding protein (IL18BP) and its isoforms.
• To assess the binding affinity and neutralizing capacity of different IL18BP isoforms for IL18.
• To explore the potential therapeutic applications of high-affinity IL18BP in human diseases.

Main Methods:

• Isolation and purification of naturally occurring IL18BP from healthy human urine.
• Expression and purification of various human and mouse IL18BP isoforms.
• Binding assays (on-rate, off-rate, dissociation constant) and neutralization assays to assess IL18-IL18BP interactions.
• Molecular modeling to identify the IL18 binding site on IL18BP.

Main Results:

• Two human IL18BP isoforms with complete immunoglobulin domains showed high affinity for IL18 (dissociation constant of 399 pM).
• These high-affinity isoforms rapidly neutralized >95% of IL18 at a molar excess of two.
• Other isoforms with incomplete immunoglobulin domains were unable to neutralize IL18.
• Molecular modeling revealed a mixed electrostatic and hydrophobic binding site responsible for high-affinity binding.

Conclusions:

• IL18BP is a secreted protein that effectively neutralizes IL18, thereby suppressing IFNγ production and T-helper type 1 immune responses.
• Specific human IL18BP isoforms with complete immunoglobulin domains exhibit high-affinity binding and potent IL18 neutralization.
• These high-affinity IL18BP forms represent potential therapeutic agents for diseases involving IL18 dysregulation.