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

Bufler, Philip; Azam, Tania; Gamboni‐Robertson, Fabia; Reznikov, Leonid L.; Kumar, Sanjay; Dinarello, Charles A.; Kim, Soohyun

doi:10.1073/pnas.212519099

Cited by 221 publications

(265 citation statements)

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“…Thus, it is likely that the alternate splicing, leading to the generation of D3pro-IL-18, may represent a regulatory mechanism that inhibits the production of biologically active IL-18 in some ovarian tumors. In this context, it should be outlined that similar to the IL-1b/IL-1R system, the IL-18/IL-18R system also has several natural inhibitors which may negatively regulate the IL-18 biological activity, protecting the organism from unappropriate IL-18-mediated damage (Novick et al, 1999;Kim et al, 2000;Young et al, 2000;Xiang and Moss, 2001;Bufler et al, 2002). Thus, a soluble IL-18 binding protein (BP), which prevent binding of mature IL-18 to its receptor, and inhibits IL-18 biological activity has been identified Figure 6 D3pro-IL-18 binds to caspase-1.…”

Section: Discussionmentioning

confidence: 99%

“…Four isoforms of this IL-18 BP, displaying differential ability to bind and inhibit IL-18 activity exists in humans (Kim et al, 2000), and a poxvirus-encoded IL-18 BP analog displaying similar inhibitory activity has been described (Xiang and Moss, 2001). In addition, a IL-1b homologue (IL-1F7b) has been reported to interact with IL-18 BP and cooperate in blocking IL-18 activity (Bufler et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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A novel isoform of pro-interleukin-18 expressed in ovarian tumors is resistant to caspase-1 and -4 processing

et al. 2004

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A novel isoform of pro-interleukin-18 expressed in ovarian tumors is resistant to caspase-1 and -4 processing

et al. 2004

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“…The function of these new family members is still to be elucidated but there is evidence that some may act through IL-1RL2 and IL-1RAcP 14,15 and that IL-1F7 may be important in IL-18 antagonism. 16 The genes for the IL-1 receptor family are also located together in a cluster on chromosome 2q11.2, along with the genes for the two IL-18 receptors (IL-18R1 and IL-18RAcP) also members of the IL-1 receptor family 17 ( Figure 1). The type 1 IL-1 receptor (IL-1R1) is required for signal transduction, while the type 2 IL-1 receptor (IL-1R2) is a non-signal transducing, decoy receptor.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive association study of genetic variants in the IL-1 gene family in systemic juvenile idiopathic arthritis

et al. 2008

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Patients with systemic juvenile idiopathic arthritis (sJIA) have a characteristic daily spiking fever and elevated levels of inflammatory cytokines. Members of the interleukin-1 (IL-1) gene family have been implicated in various inflammatory and autoimmune diseases, and treatment with the IL-1 receptor antagonist, Anakinra, shows remarkable improvement in some patients. This work describes the most comprehensive investigation to date of the involvement of the IL-1 gene family in sJIA. A two-stage case-control association study was performed to investigate the two clusters of IL-1 family genes using a tagging single nucleotide polymorphism (SNP) approach. Genotyping data of 130 sJIA patients and 151 controls from stage 1 highlighted eight SNPs in the IL1 ligand cluster region and two SNPs in the IL1 receptor cluster region as showing a significant frequency difference between the populations. These 10 SNPs were typed in an additional 105 sJIA patients and 184 controls in stage 2. Meta-analysis of the genotypes from both stages showed that three IL1 ligand cluster SNPs (rs6712572, rs2071374 and rs1688075) and one IL1 receptor cluster SNP (rs12712122) show evidence of significant association with sJIA. These results indicate that there may be aberrant control of the activity of the IL-1 family in sJIA patients causing the increased susceptibility to the disease.

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“…In human peripheral blood from healthy subjects, low levels of steady-state IL-37 mRNA and protein are expressed in monocytes, dendritic cells (DCs), and plasma cells perhaps due to instability elements within the coding region (4,5); however, stimulation with proinflammatory cytokines or Toll-like receptor (TLR) ligands induces IL-37 levels, which in turn suppress the proinflammatory cytokines IL-1α, IL-1β, IL-6, M-CSF, and GM-CSF but not anti-inflammatory cytokines IL-10 and IL-1Ra (4)(5)(6)(7). Although an ORF for the murine homolog of IL37 is absent in various mouse databases, human IL-37 expression in a variety of human and murine cells inhibits innate immunity and suppresses production of proinflammatory cytokines and chemokines (2,3,8), indicating that human IL-37 is functional in murine cells.…”

mentioning

confidence: 99%

Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells

Luo¹,

Cai

Liu³

et al. 2014

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

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IL-1 family member IL-37 limits innate inflammation in models of colitis and LPS-induced shock, but a role in adaptive immunity remains unknown. Here, we studied mice expressing human IL-37b isoform (IL-37tg) subjected to skin contact hypersensitivity (CHS) to dinitrofluorobenzene. CHS challenge to the hapten was significantly decreased in IL-37tg mice compared with wild-type (WT) mice (−61%; P < 0.001 at 48 h). Skin dendritic cells (DCs) were present and migrated to lymph nodes after antigen uptake in IL-37tg mice. When hapten-sensitized DCs were adoptively transferred to WT mice, antigen challenge was greatly impaired in mice receiving DCs from IL-37tg mice compared with those receiving DCs from WT mice (−60%; P < 0.01 at 48 h). In DCs isolated from IL-37tg mice, LPS-induced increase of MHC II and costimulatory molecule CD40 was reduced by 51 and 31%, respectively. In these DCs, release of IL-1β, IL-6, and IL-12 was reduced whereas IL-10 secretion increased (37%). Consistent with these findings, DCs from IL-37tg mice exhibited a lower ability to stimulate syngeneic and allogeneic naive T cells as well as antigen-specific T cells and displayed enhanced induction of T regulatory (Treg) cells (86%; P < 0.001) in vitro. Histological analysis of CHS skin in mice receiving hapten-sensitized DCs from IL-37tg mice revealed a marked reduction in CD8 + T cells (−74%) but an increase in Treg cells (2.6-fold). Together, these findings reveal that DCs expressing IL-37 are tolerogenic, thereby impairing activation of effector T-cell responses and inducing Treg cells. IL-37 thus emerges as an inhibitor of adaptive immunity.tolerance | skin inflammation | allergic contact dermatitis I nterleukin-37 (IL-37; formerly IL-1 family member 7) isoform b inhibits innate inflammation (1-3). In human peripheral blood from healthy subjects, low levels of steady-state IL-37 mRNA and protein are expressed in monocytes, dendritic cells (DCs), and plasma cells perhaps due to instability elements within the coding region (4, 5); however, stimulation with proinflammatory cytokines or Toll-like receptor (TLR) ligands induces IL-37 levels, which in turn suppress the proinflammatory cytokines IL-1α, IL-1β, IL-6, M-CSF, and GM-CSF but not anti-inflammatory cytokines IL-10 and IL-1Ra (4-7). Although an ORF for the murine homolog of IL37 is absent in various mouse databases, human IL-37 expression in a variety of human and murine cells inhibits innate immunity and suppresses production of proinflammatory cytokines and chemokines (2,3,8), indicating that human IL-37 is functional in murine cells. Compared with WT mice, mice expressing human IL-37b (IL-37tg mice) produce lower amounts of proinflammatory cytokines after lipopolysaccharide (LPS) administration and are protected from LPS-induced septic shock (3) and dextran sulfate sodium-induced colitis (8). Administration of recombinant human IL-37 in mice suppresses cytokine and chemokine production, neutrophil infiltration, and cell death, thereby ameliorating hepatic and myocardial ischemia/reperfu...

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

Cited by 221 publications

References 28 publications

A novel isoform of pro-interleukin-18 expressed in ovarian tumors is resistant to caspase-1 and -4 processing

A novel isoform of pro-interleukin-18 expressed in ovarian tumors is resistant to caspase-1 and -4 processing

Comprehensive association study of genetic variants in the IL-1 gene family in systemic juvenile idiopathic arthritis

Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells

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