Publications about IL-1RAcP

Publication

One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β.

Journal: Journal of Molecular Biology

March/5/2013

Abstract

Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.

Authors

Michaela Blech; Daniel Peter; Peter Fischer; Margit M T Bauer; Mathias Hafner; Markus Zeeb; Herbert Nar

Publication

Role of interleukin-33 in innate-type immune cells in allergy.

Journal: Allergology International

April/18/2013

Abstract

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is preferentially and constitutively expressed in epithelial cells, and it is especially localized in the cells' nucleus. The nuclear IL-33 is released by necrotic cells after tissue injury and/or trauma, and subsequently provokes local inflammation as an alarmin, like high-mobility group box protein-1 (HMGB-1) and IL-1α. IL-33 mainly activates Th2 cells and such innate-type immune cells as mast cells, basophils, eosinophils and natural helper cells that express IL-33R (a heterodimer of IL-1 receptor-like 1 [IL-1RL1; also called ST2, T1, Der4, fit-1] and IL-1 receptor accessory protein [IL-1RAcP]). That activation causes the cells to produce Th2 cytokines, which contribute to host defense against nematodes. On the other hand, excessive and/or inappropriate production of IL-33 is also considered to be involved in the development of such disorders as allergy. In this review, we summarize current knowledge regarding the pathogenic roles of IL-33 in the development of allergic inflammation by focusing on its effects on innate-type immune cells.

Authors

Susumu Nakae; Hideaki Morita; Tatsukuni Ohno; Ken Arae; Kenji Matsumoto; Hirohisa Saito

Publication

Extracellular regulation of interleukin (IL)-1beta through lung epithelial cells and defective IL-1 type II receptor expression.

Journal: American Journal of Respiratory Cell and Molecular Biology

June/6/1999

Abstract

Interleukin (IL)-1beta is produced primarily by activated mononuclear phagocytic cells in the lung airway and functions as a potent proinflammatory cytokine. Release of IL-1beta in the airway microenvironment induces the production of proinflammatory factors from parenchymal airway cells, including IL-8. To study the regulation of lung epithelial cell responsiveness to IL-1beta, the human type II-like airway epithelial cell line A549 and primary normal human bronchial epithelial (NHBE) cells were assayed for IL-1-specific response modifiers. Specifically, the IL-1 type I receptor (IL-1RI), IL-1 type II receptor (IL-1RII), IL-1 receptor accessory protein (IL-1RAcP), and IL-1 receptor antagonist (IL-1Ra) were analyzed. Constitutive expression of IL-1RI, IL-1RAcP, and IL-1Ra was detected in both immortalized and primary human airway epithelial cells. Interestingly, a complete absence of IL-1RII expression was demonstrated under all study conditions in both A549 and NHBE cells. Both cell types were responsive to IL-1beta at concentrations as low as 50 to 500 pg/ml when measured by IL-8 release into cell supernatants. IL-1beta-induced chemokine production and release were inhibited by a 10- to 1,000-fold molar excess of recombinant IL-1RII or IL-1Ra, whereas IL-1RI was a less effective inhibitor. On the basis of our results, we propose that human lung epithelial cells lack the ability to downregulate IL-1beta activity extracellularly because of an inability to express IL-1RII. Release of extracellular IL-1 inhibitors, including soluble IL-1Ra and soluble IL-1RII, by other inflammatory cells present in the airway may be critical for regulation of IL-1beta activity in the airway microenvironment.

Authors

K R Coulter; M D Wewers; M P Lowe; D L Knoell

Publication

Interleukin-1 receptor accessory protein interacts with the type II interleukin-1 receptor.

Journal: FEBS Letters

July/28/1998

Abstract

Stably transfected HEK-293 cells express on their surface the murine type II IL-1 receptor (mIL-1RII) as demonstrated by FACS analysis using the mAb 4E2, however binding of [125I]-hrIL-1beta to these cells is nearly absent. Saturable high affinity binding of [125I]-hrIL-1beta is observed when the murine IL-1 receptor accessory protein (mIL-1RAcP) is coexpressed with mIL-1RII. Binding of [125I]-hrIL-1beta to mIL-1RII-mIL-1RAcP complex can be inhibited either with antibodies to mIL-1RII (mAb 4E2), or by antibodies to mIL-1RAcP (mAb 4C5). The number of high affinity binding sites in cells stably transfected with the cDNA for mIL-1RII is dependent on the dose of cDNA for mIL-1RAcP used to transfect the cells. The high affinity complex between mIL-1RII and mIL-1RAcP is not preformed by interaction between the intracellular domains of these two transmembrane proteins, rather it appears to require the extracellular portions of mIL-1RII and mIL-1RAcP and the presence of a ligand. We suggest that in addition to its earlier described decoy receptor role, IL-1RII may modulate the responsiveness of cells to IL-1 by binding the IL-1RAcP in unproductive/non-signalling complexes and thus reducing the number of signalling IL-1RI-IL-1RAcP-agonist complexes when IL-1 is bound.

Authors

D Malinowsky; J Lundkvist; S Layé; T Bartfai

Publication

Effectiveness of the soluble form of the interleukin-1 receptor accessory protein as an inhibitor of interleukin-1 in collagen-induced arthritis.

Journal: Arthritis and rheumatism

November/20/2003

Abstract

OBJECTIVE

To investigate whether the soluble form of interleukin-1 (IL-1) receptor accessory protein (sIL-1RAcP), whose physiologic function remains to be established, can serve as a specific inhibitor of IL-1 signaling in vitro, and to evaluate its applicability in collagen-induced arthritis (CIA).

METHODS

Soluble IL-1RAcP was cloned from murine liver complementary DNA and expressed by the use of either an adenoviral vector (AdRGD) for sIL-1RAcP or a stable-transfected NIH3T3 fibroblast cell line. The ability of affinity-purified sIL-1RAcP to inhibit IL-1 signaling was tested on NF-kappaB luciferase reporter fibroblasts and quantified by luminometer. To investigate therapeutic efficacy, sIL-1RAcP was both locally (knee joint) and systemically overexpressed in collagen-immunized male DBA/1 mice. Severity of arthritis was monitored visually, and the pathologic process in the joint was examined histologically. Serum was obtained from mice to quantify IL-6 and anti-bovine type II collagen (BCII) antibody levels.

RESULTS

Incubation of the NF-kappaB reporter fibroblast with purified sIL-1RAcP protein showed a marked reduction of IL-1-induced, but not tumor necrosis factor-induced, NF-kappaB activation. This showed a novel role for sIL-1RAcP as a specific inhibitor of IL-1 signaling. Local transplantation of sIL-1RAcP-producing NIH3T3 fibroblasts into the knee before onset of CIA had little or no effect on general disease severity in these mice. Histologic evaluation of the knee joints receiving sIL-1RAcP cell transplantation showed a marked reduction in both joint inflammation and bone and cartilage erosion. Local treatment with sIL-1RAcP had no profound effect on serum levels of IL-6 and anti-BCII antibodies, which is indicative of the ongoing presence of arthritis in distal joints. In contrast to local treatment, systemic treatment with the AdRGD for sIL-1RAcP markedly ameliorated CIA in all joints.

CONCLUSIONS

In this study we demonstrated that sIL-1RAcP is a biologically active and innovative inhibitor of IL-1, and treatment of mice with sIL-1RAcP had a profound prophylactic effect on collagen-induced arthritis.

Authors

R L Smeets; F A J van de Loo; L A B Joosten; O J Arntz; M B Bennink; W A Loesberg+4 authors

Publication

A role of IL-1R1 signaling in the differentiation of Th17 cells and the development of autoimmune diseases.

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Journal: Self/nonself

February/19/2017

Abstract

IL-1 cytokine family plays a key role in the innate immune response against pathogen- and danger-associated molecular patterns. More recently, IL-1 receptor type 1 (IL-R1) signaling has been identified as a critical step in the differentiation and commitment of Th17 cells, which mediate the development of autoimmune diseases. Given its significance in the induction of the adoptive immune response, this complex signaling pathway is tightly regulated. Upon binding of IL-1 to IL-1R1, IL-1R accessory protein (AcP) is recruited to form a high affinity IL-1R1-IL-1RAcP heterodimeric receptor, which initiates the downstream signaling cascade. Multiple negative regulators of this pathway, including inhibitory membrane-bound IL-RII, secreted soluble (s)IL-1RI, sIL-RII and sIL-1RAcP, the regulatory IL-1R1 antagonist (IL-1R1a) and the IL-1R1-signlaing-induced single Ig-IL-1R-related (SIGIRR), provide a negative feedback control of this pathway, and suppress excessive IL-1 signaling and Th17 cell differentiation. IL-1R1 signaling induces human Th17 cell differentiation, leading to the expression of IL-1R-associated protein kinase (IRAK)4 and retinoic acid-related orphan nuclear hormone receptor (ROR), Th17 cell lineage transcription factors, which together with signal transducer and activator of the transcription (STAT)3, activate this cell lineage's specific cytokine expression profile, including IL-17A, IL-17F, IL-21 and IL-22. Given the role of IL-1 signaling and Th17 cells in the development of the autoinflammatory and autoimmune diseases, therapeutic strategies inhibiting IL-1R1 signaling are discussed as a novel approach for the treatment of autoimmune diseases and particularly multiple sclerosis (MS).

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Authors

Yonggang Sha; Silva Markovic-Plese

Publication

Interleukin-1 family cytokines and their regulatory proteins in normal pregnancy and pre-eclampsia.

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Journal: Clinical and Experimental Immunology

November/16/2015

Abstract

Maternal systemic inflammation is a feature of pre-eclampsia, a condition in pregnancy characterized by hypertension and proteinuria. Pre-eclampsia is caused by the placenta; many placental factors contribute to the syndrome's progression, and proinflammatory cytokines have been identified previously as one such mediator. The interleukin (IL)-1 family of cytokines are key regulators of the inflammatory network, and two naturally occurring regulatory molecules for IL-1 family cytokines, IL-1RA and sST2, have been found previously to be elevated in maternal blood from women with pre-eclampsia. Here we investigate more recently identified IL-1 family cytokines and regulatory molecules, IL-1RAcP, IL-37, IL-18BP, IL-36α/β/γ/Ra and IL-38 in pre-eclampsia. Pregnant women have more circulating IL-18BP and IL-36Ra than non-pregnant women, and sIL-1RAcP is elevated from women with pre-eclampsia compared to normal pregnancies. The placenta expresses all the molecules, and IL-37 and IL-18BP are up-regulated significantly in pre-eclampsia placentas compared to those from normal pregnancies. Together, these changes contribute to the required inhibition of maternal systemic cytotoxic immunity in normal pregnancy; however, in pre-eclampsia the same profile is not seen. Interestingly, the increased circulating levels of sIL-1RAcP and increased placental IL-18BP and IL-37, the latter of which we show to be induced by hypoxic damage to the placenta, are all factors which are anti-inflammatory. While the placenta is often held responsible for the damage and clinical symptoms of pre-eclampsia by the research community, here we show that the pre-eclampsia placenta is also trying to prevent inflammatory damage to the mother.

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Authors

J H Southcombe; C W G Redman; I L Sargent; I Granne

Publication

Model of interaction of the IL-1 receptor accessory protein IL-1RAcP with the IL-1beta/IL-1R(I) complex.

Journal: FEBS Letters

July/25/2001

Abstract

A preliminary model has been calculated for the activating interaction of the interleukin 1 receptor (IL-1R) accessory protein IL-1RAcP with the ligand/receptor complex IL-1beta/IL-1R(I). First, IL-1RAcP was modeled on the crystal structure of IL-1R(I) bound to IL-1beta. Then, the IL-1RAcP model was docked using specific programs to the crystal structure of the IL-1beta/IL-1R(I) complex. Two types of models were predicted, with comparable probability. Experimental data obtained with the use of IL-1beta peptides and antibodies, and with mutated IL-1beta proteins, support the BACK model, in which IL-1RAcP establishes contacts with the back of IL-1R(I) wrapped around IL-1beta.

Authors

R Casadio; E Frigimelica; P Bossù; D Neumann; M U Martin; A Tagliabue; D Boraschi

Publication

Delineation of the proinflammatory cytokine cascade in fever induction.

Journal: Annals of the New York Academy of Sciences

February/4/1999

Abstract

Bacterial lipopolypolysaccharide (LPS)-induced fever involves induction of the proinflammatory cytokines interleukin (IL)-1 alpha, IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), and IL-6, both in the periphery and in the brain. These molecules can induce expression of each other and also regulate expression of their own receptors in a complex manner. The functional hierarchy of these highly inducible proteins is therefore difficult to determine. Using mice strains carrying the null mutations of IL-1 beta, IL-1RI, IL-1RAcP, or IL-6, respectively, we show that LPS-induced fever involves IL-1 beta, which acts at a complex consisting of the type I IL-1 receptor and the IL-1RAcP. This action occurs prior to central IL-6 release, which has been shown to be a necessary component of fever responses induced by LPS, IL-1 beta, and also TNF-alpha. In the absence of IL-1 beta, as in IL-1 beta-deficient mice, LPS, IL-1 alpha, and IL-1 beta cause hyperresponsive fevers when exogenously applied. Murine TNF-alpha is a poor pyrogen in mice even when mice are kept at thermoneutral temperature (30 degrees C). TNF-alpha-mediated fever depends on central IL-6 expression.

Authors

M Zetterström; A K Sundgren-Andersson; P Ostlund; T Bartfai

Publication

Human hepatitis B viral e antigen interacts with cellular interleukin-1 receptor accessory protein and triggers interleukin-1 response.

Journal: Journal of Biological Chemistry

December/20/2006

Abstract

Human hepatitis B virus (HBV) can cause acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV e antigen (HBeAg), a secreted protein and not required for viral replication, is thought to play an immunoregulatory role during viral infection. However, the functional involvement of HBeAg in host immune response has not been fully elucidated. We report in this study that HBeAg can bind to interleukin-1 receptor accessory protein (IL-1RAcP). Interleukin-1 (IL-1) plays an important role in inflammation and regulation of immune response, and membrane form of IL-1RAcP (mIL-1RAcP) is an essential component of trimeric IL-1/IL-1 receptor/mIL-1RAcP complex. We show that glutathione S-transferase- or polyhistidine-tagged recombinant HBeAg can interact with endogenous mIL-1RAcP in vitro. Purified (His)6-HBeAg added in the culture medium can interact with overexpressed FLAG-tagged mIL-1RAcP in vivo. Indirect immunofluorescence and confocal microscopy show that HBeAg colocalizes with mIL-1RAcP on the cell surface. Furthermore, HBeAg is able to induce the interaction of IL-1 receptor I (IL-1RI) with mIL-1RAcP and trigger the recruitment of adaptor protein myeloid differentiation factor 88 (MyD88) to the IL-1RI/mIL-1RAcP complex. Assembly and activation of IL-1RI/mIL-1RAcP signaling complex by HBeAg can activate downstream NF-kappaB pathway through IkappaB degradation, induce NF-kappaB-dependent luciferase expression, and induce the expression of IL-1-responsive genes. Silencing of IL-1RAcP by small interfering RNA dramatically abolishes HBeAg-mediated NF-kappaB activation. These results demonstrate that HBeAg can trigger host IL-1 response by binding to mIL-1RAcP. The interaction of HBeAg with mIL-1RAcP may play an important role in modulating host immune response in acute and chronic HBV infection.

Authors

Chih-Yung Yang; Tzu-Hsing Kuo; Ling-Pai Ting

Publication

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

Journal: Arthritis and rheumatism

August/15/2005

Abstract

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 sIL-1RAcP or IL-1Ra were administered systemically before onset of collagen-induced arthritis in DBA/1 mice. Anti-bovine 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-kappaB 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 sIL-1RAcP 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-kappaB reporter mice, we showed that sIL-1RAcP inhibits IL-1-induced NF-kappaB 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-kappaB 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.

CONCLUSIONS

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.

Authors

R L Smeets; L A B Joosten; O J Arntz; M B Bennink; N Takahashi; H Carlsen+3 authors

Publication

How to handle adsorption of cerebrospinal fluid amyloid β (1-42) in laboratory practice? Identifying problematic handlings and resolving the issue by use of the Aβ42/Aβ40 ratio.

Journal: Alzheimer's and Dementia

August/10/2017

Abstract

BACKGROUND

We aimed to investigate factors defining amyloid β (1-42) (Aβ1-42) adsorption during preanalytical workup of cerebrospinal fluid (CSF).

METHODS

CSF was transferred to new tubes ≤4 times. Variables tested were different polypropylene tube brands, volumes, CSF Aβ1-42 concentrations, incubation times, pipettes, vortex intensities, and other CSF proteins, including hyperphosphorylated tau and Interleukin 1 Receptor Accessory Protein (IL-1RAcP). An enquiry assessed the number of transfers in current practice.

RESULTS

In diagnostic practice, the number of transfers varied between 1 and 3. Every tube transfer resulted in 5% loss of Aβ1-42 concentration, even 10% in small volumes. Adsorption was observed after 30 seconds and after contact with the pipette tip. Tube brand, vortexing, or continuous tube movement did not influence adsorption. Adsorption for Aβ1-40 was similar, resulting in stable Aβ1-42/Aβ1-40 ratios over multiple tube transfers.

CONCLUSIONS

We confirmed that adsorption of CSF Aβ1-42 during preanalytical processing is an important confounder. However, use of the Aβ1-42/Aβ1-40 ratio overcomes this effect and can therefore contribute to increased diagnostic accuracy.

Authors

Eline Willemse; Kees van Uffelen; Britta Brix; Sebastiaan Engelborghs; Hugo Vanderstichele; Charlotte Teunissen

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Publication

Activation of acid sphingomyelinase by interleukin-1 (IL-1) requires the IL-1 receptor accessory protein.

Journal: Journal of Biological Chemistry

December/8/1997

Abstract

The cytokine interleukin-1 (IL-1) plays an important role in inflammation and regulation of immune responses, but the mechanisms of its signal transduction and cell activation processes are incompletely understood. Ceramide generated by sphingomyelinases (SMases) is known to function as an important second messenger molecule in the signaling pathway of IL-1 and tumor necrosis factor. To investigate the activation of SMases by IL-1, we used an IL-1 receptor type I (IL-1RI)-positive EL4 thymoma cell line, which is defective in IL-1R accessory protein (IL-1RAcP) expression. In this cell line (EL4D6/76), tumor necrosis factor induced ligand/receptor internalization, NFkappaB nuclear translocation, IL-2 production, and the activation of neutral (N)-SMase and acid (A)-SMase. In contrast, stimulation with IL-1 resulted only in the activation of N-SMase whereas ligand/receptor internalization, NFkappaB translocation, IL-2 production, and activation of A-SMase were not detected. Transfection of this functionally defective EL4D6/76 with IL-1RAcP cDNA restored these functions. These data suggest that A-SMase activity is strongly linked with the internalization of IL-1RI mediated by IL-1RAcP and that A-SMase and N-SMase are activated by different pathways.

Authors

R Hofmeister; K Wiegmann; C Korherr; K Bernardo; M Krönke; W Falk

Publication

The potential role of IL-33/ST2 signaling in fibrotic diseases.

Journal: Journal of Leukocyte Biology

September/29/2015

Abstract

IL-33, a new member of the IL-1F, is widely expressed throughout the body and can be up-regulated by stimulation with proinflammatory factors. It has been identified as a functional ligand for the plasma membrane receptor complex that is a heterodimer consisting of membrane-bound ST2L, which is a member of the IL-1R family, and IL-1RAcP. IL-33 is crucial for the induction of Th2 immune responses. Additionally, under other circumstances, it can also act as an endogenous danger signal. Recently, many studies have demonstrated that IL-33 may be related to the development and progression of fibrotic diseases. It has proinflammatory effects in some fibrotic diseases but has anti-inflammatory effects in others. In this review, the biologic characteristics of IL-33 and the role of the IL-33/ST2 signaling pathway in various fibrotic diseases will be discussed. We hope this overview will provide new insights for the treatment of these diseases.

Authors

Qiaoyan Gao; Yan Li; Mingcai Li

Publication

Inhibition of IL-1 Signaling by Antisense Oligonucleotide-mediated Exon Skipping of IL-1 Receptor Accessory Protein (IL-1RAcP).

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Journal: Molecular Therapy - Nucleic Acids

January/23/2013

Abstract

The cytokine interleukin 1(IL-1) initiates a wide range of proinflammatory cascades and its inhibition has been shown to decrease inflammation in a variety of diseases. IL-1 receptor accessory protein (IL-1RAcP) is an indispensible part of the IL-1R complex that stabilizes IL-1/IL-1R interaction and plays an important role in the signal transduction of the receptor complex. The soluble form of IL-1RAcP (sIL-1RAcP) contains only the extracellular domain and serves as a natural inhibitor of IL-1 signaling. Therefore, increasing sIL-1RAcP levels might be an attractive therapeutic strategy to inhibit IL-1-driven inflammation. To achieve this we designed specific antisense oligonucleotides (AON), to redirect pre-mRNA IL-1RAcP splicing by skipping of the transmembrane domain encoding exon 9. This would give rise to a novel Δ9IL-1RAcP mRNA encoding a soluble, secreted form of IL-1RAcP, which might have similar activity as natural sIL-1RAcP. AON treatment resulted in exon 9 skipping both in vitro and in vivo. A single dose injection of 10 mg AON/kg body weight induced 90% skipping in mouse liver during at least 5 days. The truncated mRNA encoded for a secreted, soluble Δ9IL-1RAcP protein. IL-1RAcP skipping resulted in a substantial inhibition of IL-1 signaling in vitro. These results indicate that skipping of the transmembrane encoding exon 9 of IL-1RAcP using specific AONs might be a promising therapeutic strategy in a variety of chronic inflammatory diseases.Molecular Therapy - Nucleic Acids (2013) 2, e66; doi:10.1038/mtna.2012.58; published online 22 January 2013.

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Authors

A Seda Yılmaz-Eliş; Annemieke Aartsma-Rus; Peter Ac 't Hoen; Huma Safdar; Cor Breukel; Bart Jm van Vlijmen+4 authors

Publication

Impact of IL-1 signalling on experimental uveitis and arthritis.

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Journal: Annals of the Rheumatic Diseases

May/30/2012

Abstract

BACKGROUND

Uveitis, or inflammatory eye disease, is a common extra-articular manifestation of many systemic autoinflammatory diseases involving the joints. Anakinra (recombinant interleukin (IL)-1 receptor antagonist (Ra)) is an effective therapy in several arthritic diseases; yet, few studies have investigated the extent to which IL-1 signalling or IL-1Ra influences the onset and/or severity of uveitis.

OBJECTIVE

To seek possible links between arthritis and uveitis pathogenesis related to IL-1 signalling.

METHODS

The eyes of IL-1Ra-deficient BALB/c mice were monitored histologically and by intravital videomicroscopy to determine if uveitis developed along with the expected spontaneous arthritis in ankles and knees. Expression levels of IL-1R and its negative regulators (IL-1Ra, IL-1RII, IL-1RAcP and single Ig IL-1R-related molecule) in eye and joint tissues were compared. Differences in uveitis induced by intraocular injection of lipopolysaccharide (LPS) in mice lacking IL-1R or IL-1Ra were assessed.

RESULTS

Deficiency in IL-1Ra predisposes to spontaneous arthritis, which is exacerbated by previous systemic LPS exposure. The eye, however, does not develop inflammatory disease despite the progressive arthritis or LPS exposure. Organ-specific expression patterns for IL-1Ra and negative regulators of IL-1 activity were observed that appear to predict predisposition to inflammation in each location in IL-1Ra knockout mice. The eye is extremely sensitive to locally administered LPS, and IL-1Ra deficiency markedly exacerbates the resulting uveitis.

CONCLUSIONS

This study demonstrates that IL-1Ra plays an important role in suppressing local responses in eyes injected with LPS and that there is discordance between murine eyes and joints in the extent to which IL-1Ra protects against spontaneous inflammation.

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Authors

Stephen R Planck; April Woods; Jenna S Clowers; Martin J Nicklin; James T Rosenbaum; Holly L Rosenzweig

Publication

Characterization of ST2 transgenic mice with resistance to IL-33.

Journal: European Journal of Immunology

November/2/2010

Abstract

IL-33, a member of the IL-1 family, activates MAPK and NF-kappaB through its receptor ST2L and IL-1RAcP. ST2, a member of the IL-1R superfamily, is a secreted form of ST2 gene products, which has been shown to act as a decoy receptor for IL-33 and to inhibit the IL-33/ST2L/IL-1RAcP signaling pathway. In this work, we generated ST2 transgenic mice. In control mice, intraperitoneal administration of IL-33 caused an increased number of eosinophils in blood and in peritoneal cavity, an increased number of peritoneal M Phi, splenomegaly, accumulation of periodic acid-Schiff-positive material in the lung, and high concentrations of serum IL-5 and IL-13. However, these alterations were hardly detectable in ST2 Tg mice. In peritoneal M Phi from IL-33-stimulated mice, mRNA expression of M2 M Phi marker genes were increased compared with thioglycollate-elicited peritoneal M Phi. The IL-33-stimulation also increased the secretion of IL-6 from M Phi. However, when the IL-33 was preincubated with ST2 prior to its addition to the M Phi cultures, the secretion of IL-6 was attenuated. These data suggest that, though IL-33 induced the Th2-type immune responses and infiltration of M2 type M Phi into the peritoneal cavity, ST2 can downregulate these reactions both in vivo and in vitro.

Authors

Hiromi Ohto-Ozaki; Kenji Kuroiwa; Naoko Mato; Yasushi Matsuyama; Morisada Hayakawa; Hiroyuki Tamemoto; Shin-ichi Tominaga

Publication

Noradrenaline induces IL-1ra and IL-1 type II receptor expression in primary glial cells and protects against IL-1beta-induced neurotoxicity.

Journal: European Journal of Pharmacology

February/16/2010

Abstract

The pro-inflammatory cytokine interleukin-1beta (IL-1beta) plays a key role in initiating an immune response within the central nervous system (CNS), and is thought to be a significant contributor to the neurodegenerative process. The actions of IL-1beta can be regulated by interleukin-1 receptor antagonist (IL-1ra), which prevents IL-1beta from acting on the IL-1 type I receptor (IL-1RI). Another negative regulator of the IL-1 system is the IL-1 type II receptor (IL-1RII); a decoy receptor that serves to sequester IL-1. Consequently, pharmacological strategies that tip the balance in favour of IL-1ra and IL-1RII may be of therapeutic benefit. Evidence suggests that the neurotransmitter noradrenaline elicits anti-inflammatory actions in the CNS, and consequently may play an endogenous neuroprotective role. Here we report that noradrenaline induces production of IL-1ra and IL-1RII from primary rat mixed glial cells. In contrast, noradrenaline did not alter IL-1beta expression, or expression of IL-1RI or the IL-1 type I receptor accessory protein (IL-1RAcp); both of which are required for IL-1 signalling. Our results demonstrate that the ability of noradrenaline to induce IL-1ra and IL-1RII is mediated via beta-adrenoceptor activation and downstream activation of protein kinase A and extracellular signal-regulated kinase (ERK). In parallel with its ability to increase IL-1ra and IL-1RII, noradrenaline prevented neurotoxicity in cortical primary neurons induced by conditioned medium from IL-1beta treated mixed glial cells. These data indicate that noradrenaline negatively regulates IL-1 system in glial cells and has neuroprotective properties in situations where IL-1 contributes to pathology.

Authors

Eoin N McNamee; Karen M Ryan; Dana Kilroy; Thomas J Connor

Publication

Interleukin-36 potently stimulates human M2 macrophages, Langerhans cells and keratinocytes to produce pro-inflammatory cytokines.

Journal: Cytokine

November/6/2017

Abstract

Interleukin (IL)-36 cytokines belong to the IL-1 family and include three agonists, IL-36 α, β and γ and one inhibitor, IL-36 receptor antagonist (IL-36Ra). IL-36 and IL-1 (α and β) activate similar intracellular pathways via their related heterodimeric receptors, IL-36R/IL-1RAcP and IL-1R1/IL-1RAcP, respectively. However, excessive IL-36 versus IL-1 signaling induces different phenotypes in humans, which may be related to differential expression of their respective receptors. We examined the expression of IL-36R, IL-1R1 and IL-1RAcP mRNA in human peripheral blood, tonsil and skin immune cells by RT-qPCR. Monocyte-derived dendritic cells (MDDC), M0, M1 or M2-polarized macrophages, primary keratinocytes, dermal macrophages and Langerhans cells (LC) were stimulated with IL-1β or IL-36β. Cytokine production was assessed by RT-qPCR and immunoassays. The highest levels of IL-36R mRNA were found in skin-derived keratinocytes, LC, dermal macrophages and dermal CD1a(+) DC. In the blood and in tonsils, IL-36R mRNA was predominantly found in myeloid cells. By contrast, IL-1R1 mRNA was detected in almost all cell types with higher levels in tonsil and skin compared to peripheral blood immune cells. IL-36β was as potent as IL-1β in stimulating M2 macrophages, keratinocytes and LC, less potent than IL-1β in stimulating M0 macrophages and MDDC, and exerted no effects in M1 and dermal macrophages. Levels of IL-1Ra diminished the ability of M2 macrophages to respond to IL-1. Taken together, these data are consistent with the association of excessive IL-36 signaling with an inflammatory skin phenotype and identify human LC and M2 macrophages as new IL-36 target cells.

Authors

Damien Dietrich; Praxedis Martin; Vincent Flacher; Yu Sun; David Jarrossay; Nicolo Brembilla+5 authors

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Citations(10)Authors(11)Affiliates(5)

Publication

Concordant and discordant interleukin-1-mediated signaling in lung fibroblast thy-1 subpopulations.

Journal: American Journal of Respiratory Cell and Molecular Biology

July/2/2002

Abstract

Following lung injury or inflammation, fibroblasts mediate either restorative repair or disordered remodeling. Interleukin (IL)-1beta is a key mediator in the transition from injury/inflammation to tissue remodeling, in part through its regulation of platelet-derived growth factor alpha receptor (PDGFalphaR). Based on prior demonstration of differential PDGFalphaR expression, we hypothesized that subpopulations of fibroblasts would have heterogeneous responses to IL-1. We report that IL-1beta significantly increases expression of PDGFalphaR in Thy-1-, but not Thy-1+ fibroblasts. Higher baseline expression of PDGFalphaR in Thy-1- fibroblasts is partially abrogated by IL-1 receptor antagonist. There are no differences in IL-1beta binding, as determined by flow cytometry, or in the presence of the type I IL-1 receptor (IL-1RtI) or its associated protein (IL-1RacP) by immunoblotting. IL-1beta induces DNA binding of both nuclear factor kappaB (NF-kappaB) and CAATT-enhancer binding protein (C/EBP), and activation of p38 mitogen-activated protein kinase in both subpopulations. However, IL-1beta-induced proliferation and expression of IL-6 are significantly higher in Thy-1- fibroblasts. Heterogeneous responses to IL-1beta despite equivalent presence of both proximal and distal signaling components indicates that parallel signaling pathways are activated selectively in Thy-1- cells, suggesting a prominent role for this subset in the transition from inflammation to lung remodeling.

Authors

James S Hagood; Anandit Mangalwadi; Benliu Guo; Mark W MacEwen; Lorena Salazar; Gerald M Fuller

Publication

Tuning inflammation and immunity by the negative regulators IL-1R2 and IL-1R8.

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Journal: Immunological Reviews

July/16/2018

Abstract

Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) are key players in immunity and inflammation and are tightly regulated at different levels. Most cell types, including cells of the innate and adaptive immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL-1R2 and IL-1R8 (also known as TIR8 or SIGIRR) are members of the ILR family acting as negative regulators of the IL-1 system. IL-1R2 binds IL-1 and the accessory protein IL-1RAcP without activating signaling and can be released as a soluble form (sIL-1R2), thus modulating IL-1 availability for the signaling receptor. IL-1R8 dampens ILR- and TLR-mediated cell activation and it is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R2 and IL-1R8, focusing on their role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation. We also address the emerging evidence regarding the role of IL-1R8 as a crucial checkpoint molecule in NK cells in anti-cancer and antiviral activity and the potential therapeutic implications of IL-1R8 blockade in specific pathological contexts.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922415/bin/emss-77409-f002.jpg

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922415/bin/emss-77409-f003.jpg

Authors

Martina Molgora; Domenico Supino; Alberto Mantovani; Cecilia Garlanda

Publication

Interleukin-36 in Infectious and Inflammatory Skin Diseases.

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Journal: Frontiers in Immunology

June/13/2019

Abstract

Interleukin-36 (IL-36) comprises to a cytokine family consisting of four isoforms IL-36α, IL-36β, IL-36γ, and IL-36 receptor antagonist (IL-36 Ra). These IL-36 cytokines, in turn, belong to the IL-1 superfamily. The IL-36 receptor (IL-1R6) is functional as a heterodimer formed of IL-1R6 and IL-1 receptor accessory protein (IL-1RAcP). IL-36α, IL-36β, and IL-36γ are regarded as pro-inflammatory ligands and IL-36 Ra as well as IL-38 as anti-inflammatory ligands of IL-1R6. IL-36 cytokines are mainly expressed on the barrier sites of the body e.g., bronchial, intestinal, and dermal epithelium. One of their most important biological functions is the bridging of innate and adaptive immune responses. A disturbed balance between pro-inflammatory and anti-inflammatory branches easily leads to inflammation of the corresponding tissue. The most prominent example for an altered IL-36 expression is the spectrum of psoriasis. In addition to inflammatory dermatoses, IL-36 also seems to play a role in infectious dermatoses. Microbial triggers, especially Staphylococcus aureus infection, increase the production of pro-inflammatory IL-36 cytokines and initiate/promote the inflammation of skin lesions. Due to the discovery of IL-36 as an important immune mediator, it has already been possible to develop important diagnostic tools for dermatitis. Not only in the field of inflammatory skin diseases, but also in pulmonary and intestinal inflammation, there is evidence that IL-36 cytokines might have diagnostic and/or therapeutic relevance.

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Authors

Anna-Lena Buhl; Joerg Wenzel

Publication

The 3' untranslated region of the membrane-bound IL-1R accessory protein mRNA confers tissue-specific destabilization.

Journal: Journal of Immunology

December/16/2004

Abstract

IL-1alpha and IL-1beta are proinflammatory cytokines that promote activation of intracellular signaling cascades, leading to stabilization of certain mRNAs and activation of transcription factors. IL-1R type I (IL-1RI) binds IL-1alpha and IL-1beta, and subsequent recruitment of the membrane-bound IL-1R accessory protein (mIL-1RAcP) facilitates signal transduction. Two alternatively spliced isoforms, soluble IL-1RAcP (sIL-1RAcP) and sIL-1RAcP-beta, which lack transmembrane and intracellular domains, have been described. The sIL-1RAcP and possibly sIL-1RAcP-beta can inhibit IL-1 signaling. Proportional expression of the different IL-1RAcP splice variants may be an important determinant of responsiveness to IL-1. We show that although both mIL-1RAcP and sIL-1RAcP mRNAs are widely expressed in human tissue, their relative proportions differ significantly in a tissue-specific manner. Turnover studies revealed that the sIL-1RAcP mRNA has a half-life of approximately 48 h in both the kidney cell line 293 and the hepatoma cell line HepG2. The mIL-1RAcP mRNA has a similar half-life in 293 cells, but a considerably shorter half-life of approximately 5 h in HepG2 cells. Using luciferase reporter constructs, we demonstrated that this specific destabilization of the mIL-1RAcP mRNA in the latter cell type is mediated by its 2.8-kb 3'-untranslated region. Deletion analysis further established that the cell line-specific instability does not involve AU-rich elements, but is mediated by several novel elements that appear to act independently; such elements may be recognized by proteins expressed specifically in some, but not all, tissues. These data demonstrate that the cellular capacity to respond to IL-1 is tightly regulated in a tissue-specific manner.

Authors

Liselotte E Jensen; Alexander S Whitehead

Publication

Interleukin 1 receptor accessory protein (IL-1RAcP) is necessary for centrally mediated neuroendocrine and immune responses to IL-1beta.

Journal: Journal of Neuroimmunology

November/12/2000

Abstract

Mice deficient for the IL-1RAcP gene (IL-1RAcP KO) were used to explore the role of IL-1RAcP in physiological functions of brain IL-1beta. Animals were injected i.c.v. with two different doses of recombinant human (rh) IL-1beta: a small one (750 pg) known to induce sickness behavior, and a larger one (50 ng), chosen to counteract the possible loss of affinity of IL-1beta on its receptor. Neuroendocrine and immune parameters were measured 2 h after IL-1 injection. The increase of plasma corticosterone induced by rhIL-1beta in wild-type (WT) mice was not observed in IL-1RAcP KO mice. Likewise, the depression of splenocyte proliferation occurred in WT but not in KO mice. Finally, in opposition to WT mice, plasma levels and brain cortical content of IL-6 in IL-1RAcP KO mice remained unchanged as compared to saline-injected controls. The results clearly demonstrate that IL-1RAcP is necessary for the induction of the main neuroendocrine and immune effects of central IL-1beta.

Authors

S Liège; S Layé; K S Li; E Moze; P J Neveu