Dataset Information

Interleukin-18 Binding Protein in Immune Regulation and Autoimmune Diseases.

ABSTRACT: Natural soluble antagonist and decoy receptor on the surface of the cell membrane are evolving as crucial immune system regulators as these molecules are capable of recognizing, binding, and neutralizing (so-called inhibitors) their targeted ligands. Eventually, these soluble antagonists and decoy receptors terminate signaling by prohibiting ligands from connecting to their receptors on the surface of cell membrane. Interleukin-18 binding protein (IL-18BP) participates in regulating both Th1 and Th2 cytokines. IL-18BP is a soluble neutralizing protein belonging to the immunoglobulin (Ig) superfamily as it harbors a single Ig domain. The Ig domain is essential for its binding to the IL-18 ligand and holds partial homology to the IL-1 receptor 2 (IL-1R2) known as a decoy receptor of IL-1α and IL-1β. IL-18BP was defined as a unique soluble IL-18BP that is distinct from IL-18Rα and IL-18Rβ chain. IL-18BP is encoded by a separated gene, contains 8 exons, and is located at chr.11 q13.4 within the human genome. In this review, we address the difference in the biological activity of IL-18BP isoforms, in the immunity balancing Th1 and Th2 immune response, its critical role in autoimmune diseases, as well as current clinical trials of recombinant IL-18BP (rIL-18BP) or equivalent.

SUBMITTER: Park SY

PROVIDER: S-EPMC9313042 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Interleukin-18 Binding Protein in Immune Regulation and Autoimmune Diseases.

Park Seung Yong SY Hisham Yasmin Y Shin Hyun Mu HM Yeom Su Cheong SC Kim Soohyun S

Biomedicines 20220720 7

Natural soluble antagonist and decoy receptor on the surface of the cell membrane are evolving as crucial immune system regulators as these molecules are capable of recognizing, binding, and neutralizing (so-called inhibitors) their targeted ligands. Eventually, these soluble antagonists and decoy receptors terminate signaling by prohibiting ligands from connecting to their receptors on the surface of cell membrane. Interleukin-18 binding protein (IL-18BP) participates in regulating both Th1 and ...[more]

PMID: 35885055

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Project description:Interleukin 18 (IL18) is a cytokine that plays an important role in inflammation as well as host defense against microbes. Mammals encode a soluble inhibitor of IL18 termed IL18 binding protein (IL18BP) that modulates IL18 activity through a negative feedback mechanism. Many poxviruses encode homologous IL18BPs, which contribute to virulence. Previous structural and functional studies on IL18 and IL18BPs revealed an essential binding hot spot involving a lysine on IL18 and two aromatic residues on IL18BPs. The aromatic residues are conserved among the very diverse mammalian and poxviruses IL18BPs with the notable exception of yatapoxvirus IL18BPs, which lack a critical phenylalanine residue. To understand the mechanism by which yatapoxvirus IL18BPs neutralize IL18, we solved the crystal structure of the Yaba-Like Disease Virus (YLDV) IL18BP and IL18 complex at 1.75 Å resolution. YLDV-IL18BP forms a disulfide bonded homo-dimer engaging IL18 in a 2∶2 stoichiometry, in contrast to the 1∶1 complex of ectromelia virus (ECTV) IL18BP and IL18. Disruption of the dimer interface resulted in a functional monomer, however with a 3-fold decrease in binding affinity. The overall architecture of the YLDV-IL18BP:IL18 complex is similar to that observed in the ECTV-IL18BP:IL18 complex, despite lacking the critical lysine-phenylalanine interaction. Through structural and mutagenesis studies, contact residues that are unique to the YLDV-IL18BP:IL18 binding interface were identified, including Q67, P116 of YLDV-IL18BP and Y1, S105 and D110 of IL18. Overall, our studies show that YLDV-IL18BP is unique among the diverse family of mammalian and poxvirus IL-18BPs in that it uses a bivalent binding mode and a unique set of interacting residues for binding IL18. However, despite this extensive divergence, YLDV-IL18BP binds to the same surface of IL18 used by other IL18BPs, suggesting that all IL18BPs use a conserved inhibitory mechanism by blocking a putative receptor-binding site on IL18.

Project description:BackgroundAltered interleukin (IL)-18 levels are associated with immune-mediated inflammatory diseases (IMIDs), but no studies have investigated their causal relationship. This study aimed to examine the causal associations between IL-18 and IMIDs.MethodsWe performed a two-sample Mendelian randomization (MR) analysis. Genetic variants were selected from genome-wide association study datasets following stringent assessments. We then used these variants as instrumental variables to estimate the causal effects of IL-18 levels on the risk of developing five common IMIDs: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ankylosing spondylitis (AS), and psoriasis. We used the inverse variance-weighted (IVW) method as the primary analysis, with sensitivity analyses performed to avoid potential bias. Reverse-direction MR analyses were performed to rule out the possibility of reverse associations.ResultsWe found that genetically determined higher circulating IL-18 levels were causally associated with a higher risk for SLE (PIVW = 0.009; OR, 1.214; 95% CI, 1.049 - 1.404) and IBD (PIVW < 0.001; OR, 1.142; 95% CI, 1.062 - 1.228), but found no significant associations of IL-18 with RA (PIVW = 0.496; OR, 1.044; 95% CI, 0.923 - 1.180), AS (PIVW = 0.021; OR, 1.181; 95% CI, 1.025 - 1.361), or psoriasis (PIVW = 0.232; OR, 1.198; 95% CI, 0.891 - 1.611). In the reverse direction, no causal relationship existed between SLE or IBD and IL-18 levels. Globally, sensitivity studies using alternative MR methods supported the results that were robust and reliable. The Cochran's Q test, MR-Egger intercept, and MR-Pleiotropy RESidual Sum and Outlier excluded the influence of heterogeneity, horizontal pleiotropy, and outliers.ConclusionsWe have demonstrated that elevated IL-18 levels increase the risk of SLE and IBD but not RA, AS, or psoriasis. The results enhanced our understanding of IL-18 in the pathology of IMIDs.

Dataset Information

Interleukin-18 Binding Protein in Immune Regulation and Autoimmune Diseases.

Publications

Interleukin-18 Binding Protein in Immune Regulation and Autoimmune Diseases.

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