Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18

Kim, Soo Hyun; Eisenstein, Miriam; Reznikov, Leonid L.; Fantuzzi, Giamila; Novick, Daniela; Rubinstein, Menachem; Dinarello, Charles A.

doi:10.1073/pnas.97.3.1190

Cited by 306 publications

(316 citation statements)

References 24 publications

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“…The second neutralizing agent used was rhIL-18BP isoform a, which was labeled at the N-terminal with six histamines (rhIL-18BPa-6his). This was expressed in Chinese hamster ovary cells and purified to homogeneity (21), then injected intraperitoneally daily for 7 days at four different concentrations: 0.25, 0.5, 1, and 3 mg/kg; in this protocol, the control mice received vehicle only (0.9 % NaCl).…”

Section: Methodsmentioning

confidence: 99%

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Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis

Plater-Zyberk¹,

Joosten²,

Helsen³

et al. 2001

J. Clin. Invest.

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109

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Section: Methodsmentioning

confidence: 99%

“…IL-18BP binds IL-18 with high affinity (400 pM), and blocks its biological activity at a 1:1 molar ratio (21). Such a naturally occurring molecule represents an interesting inhibitor for testing in experimental models of disease.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis

Plater-Zyberk¹,

Joosten²,

Helsen³

et al. 2001

J. Clin. Invest.

Self Cite

109

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“…IL-18BP is a secreted protein that binds IL-18 with high affinity and prevents its interaction with the IL-18R. Different isoforms of IL-18BP have been demonstrated, four in human and two in the murine system, and biological activity is limited to particular isoforms (20).…”

Section: Il-18 Binding Protein Protects Against Contact Hypersensitivitymentioning

confidence: 99%

IL-18 Binding Protein Protects Against Contact Hypersensitivity

Plitz¹,

Saint-Mézard

Satho

et al. 2003

The Journal of Immunology

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Allergic contact dermatitis, the clinical manifestation of contact hypersensitivity, is one of the most common disorders of the skin. It is elicited upon multiple cutaneous re-exposure of sensitized individuals to the sensitizing agent. In this study, we demonstrate that using IL-18 binding protein (IL-18BP) to neutralize IL-18 significantly reduced clinical symptoms in a murine model of contact hypersensitivity. Furthermore, IL-18BP alleviated the relapses during established disease, as indicated by significant protection during re-exposure of mice that had previously undergone a contact hypersensitivity response without treatment. Although edema was not influenced, IL-18BP reduced the number of T cells homing to sites of inflammation, resulting in diminished local production of IFN-γ. Thus, by preventing the accumulation of effector T cells to the target tissue, IL-18BP appears to be a potent protective mediator to counter skin inflammation during contact hypersensitivity. Taken together with the evidence that IL-18 is present in tissue samples of the human disease, our data reinforces IL-18BP as a candidate for this therapeutic indication.

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“…I nterleukin-18 is a member of the IL-1 family and shares the common structure of IL-1 family members (1)(2)(3). IL-18 also shares cell signaling with IL-1 family members, recruiting IL-1R-associated kinases, the formation of the IL-1R-associated kinase complexes with the TNF receptor-associated factor-6, and activation of the cascade of I B␣/NF-B (4 -6).…”

Section: Identification Of a Critical Ig-like Domain In Il-18 Receptomentioning

confidence: 99%

“…Both chains of the IL-18R belong to the IL-1R family and consist of three Ig-like domains in the extracellular region (17)(18)(19). IL-18-binding protein (IL-18BP) 3 is not a part of the IL-18 signaling complex, but, rather, antagonizes IL-18 activity (2,20). It is a unique, secreted receptor-like molecule and consists of a single Ig-like domain.…”

Section: Identification Of a Critical Ig-like Domain In Il-18 Receptomentioning

confidence: 99%

Identification of a Critical Ig-Like Domain in IL-18 Receptor α and Characterization of a Functional IL-18 Receptor Complex

Azam

Novick

Bufler

et al. 2003

The Journal of Immunology

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Steady state mRNA levels in various human tissues reveal that the proinflammatory cytokine IL-18 is constitutively and ubiquitously expressed. However, limited IL-18R α-chain (IL-18Rα) expression in tissues may restrict ligand-acting sites and contribute to a specific response for IL-18. To study the IL-18R complex, [125I]IL-18 was studied for binding to the cell surface receptors of IL-18-responsive NK and macrophagic KG-1 cells. After cross-linking, [125I]IL-18 formed three IL-18R complexes with sizes of approximately 93, 160, and 220 kDa. In KG-1 cells, Scatchard analysis revealed the presence of 135 binding sites/cell, with an apparent dissociation constant (Kd) of 250 pM; in NK cells, there were 350 binding sites per cell with an apparent Kd of 146 pM. Each domain of extracellular IL-18Rα was cloned and individually expressed in Escherichia coli. An mAb specifically recognized the membrane-proximal third domain; this mAb blocked IL-18-induced IFN-γ production in NK cells. Furthermore, deletion of the membrane-proximal third domain of IL-18Rα prevented the formation of IL-18R ternary complex with IL-18R β-chain. The present studies demonstrate that the biologically active IL-18R complex requires the membrane-proximal third Ig-like domain in IL-18Rα for the formation of IL-18R ternary complex as well as for signal transduction involved in IL-18-induced IFN-γ in NK cells.

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Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18

Cited by 306 publications

References 24 publications

Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis

Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis

IL-18 Binding Protein Protects Against Contact Hypersensitivity

Identification of a Critical Ig-Like Domain in IL-18 Receptor α and Characterization of a Functional IL-18 Receptor Complex

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