A Novel Il-18bp Elisa Shows Elevated Serum Il-18bp in Sepsis and Extensive Decrease of Free Il-18

Novick, Daniela; Schwartsburd, Boris; Pinkus, Ron; Suissa, Dan; Belzer, Ilana; Sthoeger, Zev; Keane, William F.; Chvatchko, Yolande; Kim, Soo Hyun; Fantuzzi, Giamila; Dinarello, Charles A.; Rubinstein, Menachem

doi:10.1006/cyto.2001.0914

Cited by 249 publications

(237 citation statements)

References 29 publications

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“…In fact, the enhanced neutralizing effect by IL-1F7b was observed only at molar ratio of IL-18BP to IL-18 of Ͻ0.4 and at a 10-fold molar excess of IL-1F7b to IL-18. These concentrations of the IL-18BP used to reveal inhibition of IL-18 activity are indeed those found in the circulation of healthy humans (26). Because IL-18BP has a high affinity to IL-18 (K d ϭ 400 pM) (20), the neutralizing effect of Il-18BP is Ͼ90% at equimolar concentrations of IL-18BP and IL-18, and no additional effect of IL-1F7b can be observed.…”

Section: Discussionmentioning

confidence: 79%

A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity

Bufler

Azam

Gamboni‐Robertson

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 79%

A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity

Bufler

Azam

Gamboni‐Robertson

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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221

252

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“…The detection limit of the assay was 20 pg/ml. IL-18BPa levels were determined by a sandwich ELISA of monoclonal and polyclonal antibodies (anti-IL-18BPa monoclonal antibody 582.10 and rabbit anti-recombinant IL-18BPa-His 6 serum, respectively) as previously described (11). The detection limit of the assay was 62 pg/ml.…”

Section: Methodsmentioning

confidence: 99%

Regulation of interleukin‐18 binding protein production by blood and synovial cells from patients with rheumatoid arthritis

Kawashima¹,

Novick²,

Rubinstein³

et al. 2004

Arthritis & Rheumatism

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Objective. To study the regulation of interleukin-18 binding protein (IL-18BP) production by rheumatoid arthritis (RA) or control peripheral blood mononuclear cells (PBMCs) and by RA synovial tissue cells, and to compare the levels of IL-18BP messenger RNA (mRNA) expression in whole blood from RA patients and controls.Methods. Unstimulated or phytohemagglutinin and phorbol myristate acetate (PHA/PMA)-stimulated PBMCs from 10 RA patients and 12 healthy controls and unstimulated or PHA/PMA-stimulated synovial tissue cells from 8 RA patients were cultured with or without IL-12 (1 ng/ml) and IL-18 (5 ng/ml) alone or in combination. IL-18BP and interferon-␥ (IFN␥) levels in supernatants were measured by enzyme-linked immunosorbent assay. Levels of IL-18BP and IFN␥ mRNA expression in whole blood samples from 22 RA patients and 12 healthy controls were determined by quantitative reverse transcriptase-polymerase chain reaction.Results. IL-12 decreased the basal levels of IL-18BP production by freshly isolated RA or control PBMCs, but increased those of synovial cells or PHA/ PMA-stimulated PBMCs. IL-18 alone had no direct effect on IL-18BP production by PBMCs or RA synovial cells, with or without stimulation. Unstimulated whole blood samples from RA patients showed lower levels of IL-18BP mRNA expression than those from healthy controls. Conclusion.The production of IL-18BP in response to IL-12 and IL-18 was regulated differently in blood and synovial cells. The difference appears to be related to the level of cell activation.

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“…Increased levels of IL-18 have been found in various autoimmune and inflammatory diseases including patients with heart failure and coronary artery disease where its levels correlate with disease severity [1][2][3][4][5][6]. In these patients, a concomitant increase in IL-18 binding protein (IL-18BP) is observed [6] IL-18BP is a naturally occurring inhibitor of IL-18, is detected in the plasma of healthy subjects at 10-to 20-fold molar excess over IL-18 [7], and is decreased in patients with myocardial ischemic injury and dilated cardiomyopathy. Interestingly, IL-18 shows greater affinity for IL-18BP than for IL-18R, and its binding to IL-18BP is essentially irreversible [8].…”

Section: Introductionmentioning

confidence: 99%

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

Zabalgoitia

Colston

Reddy

et al. 2008

Free Radical Biology and Medicine

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The objective of this study was to determine whether heme oxygenase-1 (HO-1) or heme metabolites exert cytoprotective effects on interleukin-18-mediated endothelial cell (EC) death. Treatment with IL-18 increased NF-κB activation, PTEN induction, suppressed Akt activation, and stimulated EC death. While ectopic expression of p65 enhanced PTEN transcription, adenoviral transduction of dnIκB-α, dnp65, or dnIKKβ was inhibitory. Furthermore, IL-18 suppressed HO-1 mRNA expression via enhanced mRNA degradation. Overexpression of HO-1, treatment with HO-1 inducer hemin or the CO donor Cobalt (III) protoporphyrin IX all reversed IL-18-mediated NF-κB activation, PTEN induction, Akt suppression, and EC death. Furthermore, hemin induced HO-1 expression, and HO-1 knockdown, HO-1 inhibition, or CO scavengers all reversed the pro-survival effects of hemin. In addition, the CO donors CORM-1 and CORM-3 and the heme metabolites biliverdin and bilirubin attenuated IL-18-induced EC death via a similar signaling pathway. IL-18 induced p38α MAPK activation, and suppressed p38β isoform expression. While p38α knockdown attenuated, p38β knockdown potentiated IL-18-mediated EC death. Hemin and HO-1 reversed IL-18-mediated p38α induction, and restored p38β levels. These results demonstrate that IL-18 suppresses HO-1 expression and induces EC death. HO-1 overexpression, HO-1 induction, or treatment with heme metabolites all reverse IL-18-mediated p38α MAPK and NF-κB activation, PTEN induction, Akt suppression, and EC death. Thus, HO-1 inducers and CO donors may have the therapeutic potential to effectively block IL-18 signaling and reduce IL-18-dependent vascular injury and inflammation.

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A Novel Il-18bp Elisa Shows Elevated Serum Il-18bp in Sepsis and Extensive Decrease of Free Il-18

Cited by 249 publications

References 29 publications

A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity

A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity

Regulation of interleukin‐18 binding protein production by blood and synovial cells from patients with rheumatoid arthritis

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

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