IL-18 Receptor β-Induced Changes in the Presentation of IL-18 Binding Sites Affect Ligand Binding and Signal Transduction

Wu, Chengbin; Sakorafas, Paul; Miller, Renee; McCarthy, Donna; Scesney, Susanne M.; Dixon, Richard J.; Ghayur, Tariq

doi:10.4049/jimmunol.170.11.5571

Cited by 45 publications

(46 citation statements)

References 27 publications

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“…The crystallographically defined 125-2H epitope is consistent with and provides a structural explanation for binding and neutralization data obtained with murine IL-18 and human/ murine IL-18 chimeras (14). In that work, 125-2H was unable to bind either to murine IL-18 or to four chimeras in which the COOH-terminal human IL-18 residues 92-193, 120 -193, 146 -193, or 177-193 were replaced by the corresponding murine sequence (Fig.…”

Section: -2h Is Specific For Human Il-18-the Human Il-18⅐125-2hmentioning

confidence: 61%

“…In that work, 125-2H was unable to bind either to murine IL-18 or to four chimeras in which the COOH-terminal human IL-18 residues 92-193, 120 -193, 146 -193, or 177-193 were replaced by the corresponding murine sequence (Fig. 5a) (14), can do so, indicating that their epitopes do not overlap each other or the 125-2H epitope. Modeling allows access to the structural basis for how IL-18 is able to bind so many partners and consequently the impact of these bound partners upon the ability of IL-18 to engage its receptor (Fig.…”

Section: -2h Is Specific For Human Il-18-the Human Il-18⅐125-2hmentioning

confidence: 99%

“…The structural basis for the unusual properties of 125-2H are unclear; the authors suggested that conformational changes in IL-18R␣ occur upon formation of the IL-18R␣/IL-18R␤ receptor, thereby altering the interactions with 125-2H (14).…”

Section: Interleukin (Il)mentioning

confidence: 99%

“…In a recent study, a potent (0.2 nM) IL-18-neutralizing murine monoclonal antibody (mAb), 125-2H, inhibited binding of IL-18 to IL-18R␣ alone but not the heterodimeric IL-18R␣/IL-18R␤ receptor complex, despite rendering the ternary complex with IL-18 non-functional (14). The structural basis for the unusual properties of 125-2H are unclear; the authors suggested that conformational changes in IL-18R␣ occur upon formation of the IL-18R␣/IL-18R␤ receptor, thereby altering the interactions with 125-2H (14).…”

Section: Interleukin (Il)mentioning

confidence: 99%

“…This structure rationalizes epitope mapping data, based on human/murine IL-18 chimeras (14), in which the primary antigenic recognition loop is located near the COOH terminus. A secondary loop bolsters the interactions between IL-18 and several 125-2H complementarity-determining regions (CDRs).…”

Section: Interleukin (Il)mentioning

confidence: 99%

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Unusual Water-mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18

Argiriadi¹,

Xiang²,

et al. 2009

Journal of Biological Chemistry

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The unique cytokine interleukin-18 (IL-18) acts synergistically with IL-12 to regulate T-helper 1 and 2 lymphocytes and, as such, seems to underlie the pathogenesis of various autoimmune and allergic diseases. Several anti-IL-18 agents are in clinical development, including the recombinant human antibody ABT-325, which is entering trials for autoimmune diseases. Given competing cytokine/receptor and cytokine/receptor decoy interactions, understanding the structural basis for recognition is critical for effective development of anti-cytokine therapies. Here we report three crystal structures: the murine antibody 125-2H Fab fragment bound to human IL-18, at 1.5 Å resolution; the 125-2H Fab (2.3 Å ); and the ABT-325 Fab (1.5 Å ). These structures, along with human/mouse IL-18 chimera binding data, allow us to make three key observations relevant to the biology and antigenic recognition of IL-18 and related cytokines. First, several IL-18 residues shift dramatically (>10 Å ) upon binding 125-2H, compared with unbound IL-18 (Kato, Z., Jee, J., Shikano, H., Mishima, M., Ohki, I., Ohnishi, H., Li, A., Hashimoto, K., Matsukuma, E., Omoya, K., Yamamoto, Y., Yoneda, T., Hara, T., Kondo, N., and Shirakawa, M. (2003) Nat. Struct. Biol. 10, 966 -971). IL-18 thus exhibits plasticity that may be common to its interactions with other receptors. Related cytokines may exhibit similar plasticity. Second, ABT-325 and 125-2H differ significantly in combining site character and architecture, thus explaining their ability to bind IL-18 simultaneously at distinct epitopes. These data allow us to define the likely ABT-325 epitope and thereby explain the distinct neutralizing mechanisms of both antibodies. Third, given the high 125-2H potency, 10 well ordered water molecules are trapped upon complex formation in a cavity between two IL-18 loops and all six 125-2H complementarity-determining regions. Thus, counterintuitively, tight and specific antibody binding may in some cases be water-mediated. Interleukin (IL)3 -18 is a proinflammatory cytokine that participates in the regulation of innate and acquired immunity (2, 3). IL-18 acts alone or in concert with IL-12 to amplify the induction of proinflammatory and cytotoxic mediators, such as interferon-␥. For example, in IL-18 knock-out mice, levels of interferon-␥ and cytotoxic T cells decrease despite the presence of IL-12. Inhibition of IL-18 activity has been found to be beneficial in several autoimmune disease animal models (e.g. collagen-induced arthritis (4) and colitis (5)). Furthermore, IL-18 expression is dramatically increased by the chronic inflammatory state extant in human autoimmune diseases, such as rheumatoid arthritis (6), multiple sclerosis (7, 8), and Crohn's disease (9). These observations suggest that blockade of IL-18 may be a useful human therapeutic modality (10).Despite functional divergence from the IL-1 cytokine family, IL-18 shares many similarities with IL-1. First, human IL-18 is synthesized as a biologically inactive 24-kDa precursor. Like IL-1␤, IL-18 is act...

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Section: -2h Is Specific For Human Il-18-the Human Il-18⅐125-2hmentioning

confidence: 61%

Section: -2h Is Specific For Human Il-18-the Human Il-18⅐125-2hmentioning

confidence: 99%

Section: Interleukin (Il)mentioning

confidence: 99%

Section: Interleukin (Il)mentioning

confidence: 99%

Section: Interleukin (Il)mentioning

confidence: 99%

See 3 more Smart Citations

Unusual Water-mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18

Argiriadi¹,

Xiang²,

et al. 2009

Journal of Biological Chemistry

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Defective phosphorylation of interleukin‐18 receptor β causes impaired natural killer cell function in systemic‐onset juvenile idiopathic arthritis

Jager¹,

Vastert²,

Beekman³

et al. 2009

Arthritis & Rheumatism

143

108

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Trans‐System Mechanisms Against Ischemic Myocardial Injury

Liu

Liang

Qin

et al. 2014

Comprehensive Physiology

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A mammalian organism possesses a hierarchy of naturally evolved protective mechanisms against ischemic myocardial injury at the molecular, cellular, and organ levels. These mechanisms comprise regional protective processes, including upregulation and secretion of paracrine cell-survival factors, inflammation, angiogenesis, fibrosis, and resident stem cell-based cardiomyocyte regeneration. There are also interactive protective processes between the injured heart, circulation, and selected remote organs, defined as trans-system protective mechanisms, including upregulation and secretion of endocrine cell-survival factors from the liver and adipose tissue as well as mobilization of bone marrow, splenic, and hepatic cells to the injury site to mediate myocardial protection and repair. The injured heart and activated remote organs exploit molecular and cellular processes, including signal transduction, gene expression, cell proliferation, differentiation, migration, mobilization, and/or extracellular matrix production, to establish protective mechanisms. Both regional and trans-system cardioprotective mechanisms are mediated by paracrine and endocrine messengers and act in coordination and synergy to maximize the protective effect, minimize myocardial infarction, and improve myocardial function, ensuring the survival and timely repair of the injured heart. The concept of the trans-system protective mechanisms may be generalized to other organ systems-injury in one organ may initiate regional as well as trans-system protective responses, thereby minimizing injury and ensuring the survival of the entire organism. Selected trans-system processes may serve as core protective mechanisms that can be exploited by selected organs in injury. These naturally evolved protective mechanisms are the foundation for developing protective strategies for myocardial infarction and injury-induced disorders in other organ systems.

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IL-18 Receptor β-Induced Changes in the Presentation of IL-18 Binding Sites Affect Ligand Binding and Signal Transduction

Cited by 45 publications

References 27 publications

Unusual Water-mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18

Unusual Water-mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18

Defective phosphorylation of interleukin‐18 receptor β causes impaired natural killer cell function in systemic‐onset juvenile idiopathic arthritis

Trans‐System Mechanisms Against Ischemic Myocardial Injury

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