A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist

Schreuder, Herman; Tardif, Chantal; Trump-Kallmeyer, Susanne; Soffientini, Adolfo; Sarubbi, Edoardo; Akeson, Ann L.; Bowlin, Terry L.; Yanofsky, Stephen D.; Barrett, Ronald W.

doi:10.1038/386194a0

Cited by 216 publications

(181 citation statements)

References 28 publications

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“…Due to the conservation of the ligand-binding domains of sIL-1RAcP, this molecule may still share the receptor complex stabilizing function, thereby acting as an inhibitor of IL-1 signaling through formation of an IL-1 trap. This action of sIL-1RAcP could therefore be distinct from IL-1Ra-mediated inhibition of IL-1 signaling, since binding of IL-1Ra to the IL-1RI does not lead to recruitment of IL-1RAcP (4,37,38). In this study, we compared the effect of both inhibitors on CIA.…”

Section: Discussionmentioning

confidence: 99%

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Smeets¹,

Joosten²,

Arntz³

et al. 2005

Arthritis & Rheumatism

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Objective. To discern the mode of interleukin-1 (IL-1) inhibition of soluble IL-1 receptor accessory protein (sIL-1RAcP) by comparison with IL-1 receptor antagonist (IL-1Ra) in arthritis.Methods. Adenoviral vectors encoding either sIL1RAcP or IL-1Ra were administered systemically before onset of collagen-induced arthritis in DBA/1 mice. Antibovine type II collagen IgG and IL-6 were quantified in serum. Proliferative response of splenic T cells was determined in the presence of sIL-1RAcP or IL-1Ra. The effect on IL-1 inhibition of recombinant sIL-1RAcP and IL-1Ra was further examined in vitro, using NF-B luciferase reporter cell lines. Quantitative polymerase chain reaction was used to determine the relative messenger RNA expression of the IL-1 receptors.Results. Adenoviral overexpression of both sIL1RAcP and IL-1Ra resulted in amelioration of the collagen-induced arthritis. Both IL-1 antagonists reduced the circulating levels of antigen-specific IgG2a antibodies, but only IL-1Ra was able to inhibit lymphocyte proliferation. By using purified lymphocyte populations derived from NF-B reporter mice, we showed that sIL-1RAcP inhibits IL-1-induced NF-B activity in B cells but not T cells, whereas IL-1Ra inhibited IL-1 on both cell types. A study in a panel of NF-B luciferase reporter cells showed that the sIL-1RAcP inhibits IL-1 signaling on cells expressing either low levels of membrane IL-1RAcP or high levels of IL-1RII.Conclusion. We show that the sIL-1RAcP ameliorated experimental arthritis without affecting T cell immunity, in contrast to IL-1Ra. Our results provide data in support of receptor competition by sIL-1RAcP as an explanation for the different mode of IL-1 antagonism in comparison with IL-1Ra.

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Section: Discussionmentioning

confidence: 99%

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Smeets¹,

Joosten²,

Arntz³

et al. 2005

Arthritis & Rheumatism

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“…Kinetics of binding of IL-1␤ to IL-1RI and IL-1RII are complex, perhaps reflecting the conformational flexibility of the receptors and the multiple binding interfaces between the cytokine and its receptors (35,36). For this reason, we used equilibrium dissociation constants (K D ) to compare the effects of XOMA 052 on the affinity of binding of IL-1␤ to these receptors.…”

Section: Resultsmentioning

confidence: 99%

Kinetic Approach to Pathway Attenuation Using XOMA 052, a Regulatory Therapeutic Antibody That Modulates Interleukin-1β Activity

Roell

Issafras

Bauer³

et al. 2010

Journal of Biological Chemistry

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Many therapeutic antibodies act as antagonists to competitively block cellular signaling pathways. We describe here an approach for the therapeutic use of monoclonal antibodies based on context-dependent attenuation to reduce pathologically high activity while allowing homeostatic signaling in biologically important pathways. Such attenuation is achieved by modulating the kinetics of a ligand binding to its various receptors and regulatory proteins rather than by complete blockade of signaling pathways. The anti-interleukin-1␤ (IL-1␤) antibody XOMA 052 is a potent inhibitor of IL-1␤ activity that reduces the affinity of IL-1␤ for its signaling receptor and co-receptor but not for its decoy and soluble inhibitory receptors. This mechanism shifts the effective dose response of the cytokine so that the potency of IL-1␤ bound by XOMA 052 is 20 -100-fold lower than that of IL-1␤ in the absence of antibody in a variety of in vitro cell-based assays. We propose that by decreasing potency of IL-1␤ while allowing binding to its clearance and inhibitory receptors, XOMA 052 treatment will attenuate IL-1␤ activity in concert with endogenous regulatory mechanisms. Furthermore, the ability to bind the decoy receptor may reduce the potential for accumulation of antibody⅐target complexes. Regulatory antibodies like XOMA 052, which selectively modulate signaling pathways, may represent a new mechanistic class of therapeutic antibodies.

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“…Recently, the molecular structure of a soluble hIL-1RI complexed with IL-1L [21], IL-1 receptor antagonist (IL-1Ra) [22] and an antagonistic peptide [23] was resolved by X-ray crystallography. The binding site for IL-1L was mapped to an area between the ¢rst two N-terminal Ig-like domains [21,23].…”

Section: Discussionmentioning

confidence: 99%

The first two N‐terminal immunoglobulin‐like domains of soluble human IL‐1 receptor type II are sufficient to bind and neutralize IL‐1β

2000

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Two forms of soluble human type II interleukin (IL)-1 receptor (shIL-1RII) were generated, one consisting of the complete extracellular three immunoglobulin (Ig)-like domains and one containing only the first two N-terminal Ig-like domains. Both forms bound IL-1L L with a dissociation constant (K d ) of 200 pM and neutralized IL-1L L in a bioassay. They did not bind or neutralize IL-1K K. This demonstrates that the two Ig-like domains of shIL-1RII are sufficient to bind IL-1L L with an affinity comparable to full length shIL-1RII. This suggests that this short form of shIL-1RII contributes to the anti-inflammatory effect of soluble IL-1 receptors in vivo. ß

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A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist

Cited by 216 publications

References 28 publications

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Kinetic Approach to Pathway Attenuation Using XOMA 052, a Regulatory Therapeutic Antibody That Modulates Interleukin-1β Activity

The first two N‐terminal immunoglobulin‐like domains of soluble human IL‐1 receptor type II are sufficient to bind and neutralize IL‐1β

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