Disease relevance of IL18BP

• Interleukin 18 and interleukin 18 binding protein: possible role in immunosuppression of chronic renal failure [1].
• Interferon-alpha induces interleukin-18 binding protein in chronic hepatitis C patients [2].
• PGE(2) production was also increased by the addition of IL-18BP to PBMC stimulated with either IL-1beta or IL-12 and also in whole blood cultures stimulated with Staphylococcus epidermidis [3].
• Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome [4].
• This was similar to human IL-18BP and the Molluscum contagiosum virus IL-18BP, which also demonstrated higher affinity for human IL-18 [5].

High impact information on IL18BP

• By neutralizing IL-18 activity with IL-18 binding protein (IL-18BP), we observed that islets produce bioactive IL-18 [6].
• In vivo, transgenic mice overproducing IL-18BP (IL-18BP-Tg) exhibited delayed hyperglycemia induced by beta cell toxic streptozotocin [6].
• The high-affinity, constitutively expressed, and circulating IL-18 binding protein (IL-18BP), which competes with cell surface receptors for IL-18 and neutralizes IL-18 activity, may act as a natural antiinflammatory as well as immunosuppressive molecule [7].
• IL-18BP treatment also preserved intracellular tissue creatine kinase levels (by 420%) [8].
• IL-18 alone had no direct effect on IL-18BP production by PBMCs or RA synovial cells, with or without stimulation [9].

Biological context of IL18BP

• OBJECTIVE: To measure serum interleukin 18 (IL18) and IL18 binding protein (IL18BP) levels in patients with inflammatory arthropathies, and to identify associations with disease status and the response to treatment [10].
• Molecular modelling identified a large mixed electrostatic and hydrophobic binding site in the immunoglobulin domain of IL18BP, which could account for its high affinity binding to the ligand [11].
• However, none of these were frequent enough to permit association studies in T1DM and we conclude that IL18BP does not contribute to the overall genetic susceptibility to type 1 diabetes [12].
• We evaluated the human IL18BP gene on chromosome 11q13 as a candidate susceptibility gene for T1DM and scanned the entire IL18BP (promoter, exons 1-6, and 3'UTR) for polymorphisms using single-strand conformational polymorphism analysis and direct sequencing [12].
• We concluded that a severe IL-18/IL-18BP imbalance results in Th-1 lymphocyte and macrophage activation, which escapes control by NK-cell cytotoxicity and may allow for secondary HPS in patients with underlying diseases [4].

Anatomical context of IL18BP

• However, unlike soluble cytokine receptors, IL18BP does not have a transmembrane domain and hence is not anchored to the cell membrane [11].
• Intestinal endothelial cells and macrophages were the major source of IL-18BP within the submucosa, and this IL-18BP production was also found to be relevant to other types of endothelial cells (HUVEC) and macrophages (peripheral monocytes) [13].
• To see whether the interleukin (IL)-18 system is operative in the endometrium, we examined the expression of IL-18, IL-18 receptor (IL-18R) and IL-18 binding protein (IL-18BP), the substance known to neutralize IL-18 activity, in this tissue [14].
• Since regulation of IL-18 activity likely contributes to the pathogenesis of inflammatory diseases as well as malignancies, we investigated gene expression of IL-18 binding protein (IL-18BP) in different human cell systems, namely in the keratinocyte cell line HaCaT, in the colon carcinoma cell line DLD-1, and in primary renal mesangial cells [15].
• Plasma levels of free IL-18 and its specific inhibitor IL-18BP were not different between the two dialyzer membranes [16].

Associations of IL18BP with chemical compounds

• Also, IL18BP treatment preserved intracellular tissue creatine kinase levels (by 420%) [17].
• The activity of IL-18 can be regulated by the IL-18-binding protein (IL-18BP), a glycoprotein of 40,000 daltons, which is constitutively expressed and appears to be the natural inhibitor of IL-18 activity [1].
• Using surface plasmon resonance, we identified seven amino acids of hIL-18BP which, when changed individually to alanine, caused an 8-750-fold decrease in binding affinity, largely because of increased off-rates [18].
• Furthermore, when the nonconserved valine of MC54L was mutated to phenylalanine, making it more like hIL-18BP, its affinity for hIL-18 increased more than 10-fold [19].
• Plasma IL-18BP was inversely correlated with creatinine clearance (correlation coefficient: -0.7479) [20].

Regulatory relationships of IL18BP

• IL-18BP reduced S. epidermidis-induced IFN-gamma (77% maximal suppression) [21].
• S. epidermidis-induced TNF-alpha was inhibited by IL-18BP and IL-1Ra, but not anti-IL-12 Ab, whereas IL-8 production was unaffected by any of the specific cytokine blocking agents [21].
• An equimolar concentration IL-18BP inhibited 90% of IL-18 activity, whereas a 4-fold molar excess of sIL-18Ralpha had no effect [22].

Other interactions of IL18BP

• CONCLUSION: The production of IL-18BP in response to IL-12 and IL-18 was regulated differently in blood and synovial cells [9].
• Unstimulated whole blood samples from RA patients showed lower levels of IL-18BP mRNA expression than those from healthy controls [9].
• IL-18BP and interferon-gamma (IFN gamma) levels in supernatants were measured by enzyme-linked immunosorbent assay [9].
• IFN-alpha administration increased IL-18BP plasma levels 3.24 fold 24 h after institution of therapy, resulting in a 67.4% reduction of free IL-18 [2].
• IL-18 signals through a two-chain receptor (IL-18R and accessory protein-like subunit, AcPL), and an inhibitory molecule, IL-18 binding protein (IL-18BP), has recently been characterized [23].

Analytical, diagnostic and therapeutic context of IL18BP

• IL18 and IL18BP were measured by enzyme linked immunosorbent assay (ELISA) [10].
• Levels of IL-18BP and IFN gamma mRNA expression in whole blood samples from 22 RA patients and 12 healthy controls were determined by quantitative reverse transcriptase-polymerase chain reaction [9].
• IL-18BP was discovered in human urine and is excreted in health following glomerular filtration [1].
• Determination of the functional epitopes of human interleukin-18-binding protein by site-directed mutagenesis [18].
• METHODS: Plasma levels of IL-18, IL-18BP and IFNgamma were measured by specific immunoassays in patients with normal kidney function (NKF, n = 29), in patients with chronic renal insufficiency (CRI, n = 29), and in patients on hemodialysis (HD, n = 40) [20].

References