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Charles A Dinarello - One of the best experts on this subject based on the ideXlab platform.
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the Interleukin 1 Family
2014Co-Authors: Charles A Dinarello, Mihai G NeteaAbstract:The biological properties of the Interleukin-1 (IL-1) Family ligands and receptors are characteristically pro-inflammatory and act as adjuvants for specific immune responses to antigen. Thus, the IL-1 Family of ligands and receptors is fundamental to innate immunity. Of the 11 members of the IL-1 Family, IL-1β has emerged as a therapeutic target for an expanding number of systemic and local inflammatory conditions termed “auto-inflammatory” diseases. These diseases are distinct from autoimmune diseases and include several hereditary conditions. Howver, auto-inflammatory diseases are also common diseases such as heart failure, gouty arthritis, and type 2 diabetes. For these, neutralization of IL-1β results in a rapid and sustained reduction in disease severity. Another member of the IL-1 Family, IL-1α, is also a mediator of inflammation but is classified as an “alarmin” because the cytokine is present in most cells and readily released upon cell death. Although treatment for autoimmune diseases often includes immunosuppressive drugs, blocking the IL-1 receptor is effective as an anti-inflammatory therapy for either IL-1α or IL-1β.
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overview of the Interleukin 1 Family of ligands and receptors
Seminars in Immunology, 2013Co-Authors: Charles A DinarelloAbstract:This issue of Seminars in Immunology on The Interleukin-1 (IL-1) Family of Ligands and Receptors updates the rapidly expanding importance of this Family. There are individual chapters on IL-1α, IL-1β, processing and secretion of IL-1β, IL-18, IL-33, IL-36 and IL-37. In addition, a chapter of IL-1 decoy receptors, IL-1 signaling receptors and the clinical applications of IL-1 blockade in human disease is included. More than any other cytokine Family, the IL-1 Family is closely linked to innate inflammatory and immune responses. This linkage is because the cytoplasmic segment of all members of IL-1 Family of receptors contains a domain, which highly homologous to the cytoplasmic domains of all Toll like receptors (TLR). This domain is termed Toll IL-1 receptor (TIR) domain and mutations in the TIR of IL-1 receptors or TLR abrogates signal transduction. Thus, fundamental responses such as the induction of cyclo-oxygenase type 2, increased surface expression of cellular adhesion molecules and increased gene expression of broad number of inflammatory molecules characterizes IL-1 signal transduction as it does for TLR agonists. Both TLR and IL-1 families non-specifically affect antigen recognition and lymphocyte function, and therefore act as helpers (adjuvants) for specific immune responses, now called acquired immunity. IL-1β is the most studied member of the IL-1 Family due to its role in mediating auto-inflammatory disease. Although the TLR and IL-1 families evolved to assist host defense against infection, the IL-1 Family also includes members that suppress inflammation, both specifically within the IL-1 Family but also non-specifically for TLR ligands and the innate immune response.
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the Interleukin 1 Family back to the future
Immunity, 2013Co-Authors: Cecilia Garlanda, Charles A Dinarello, Alberto MantovaniAbstract:Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. The IL-1 Family includes seven ligands with agonist activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ), three receptor antagonists (IL-1Ra, IL-36Ra, IL-38), and an anti-inflammatory cytokine (IL-37). Members of the IL-1 Receptor (IL-1R) Family include six receptor chains forming four signaling receptor complexes, two decoy receptors (IL-1R2, IL-18BP), and two negative regulators (TIR8 or SIGIRR, IL-1RAcPb). A tight regulation via receptor antagonists, decoy receptors, and signaling inhibitors ensures a balance between amplification of innate immunity and uncontrolled inflammation. All cells of the innate immune system express and/or are affected by IL-1 Family members. Moreover, IL-1 Family members play a key role in the differentiation and function of polarized innate and adaptive lymphoid cells. Here we will review the key properties of IL-1 Family members, with emphasis on pathways of negative regulation and orchestration of innate and adaptive immunity.
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immunological and inflammatory functions of the Interleukin 1 Family
Annual Review of Immunology, 2009Co-Authors: Charles A DinarelloAbstract:More than any other cytokine Family, the Interleukin (IL)-1 Family is closely linked to the innate immune response. This linkage became evident upon the discovery that the cytoplasmic domain of the IL-1 receptor type I is highly homologous to the cytoplasmic domains of all Toll-like receptors (TLRs). Thus, fundamental inflammatory responses such as the induction of cyclooxygenase type 2, increased expression of adhesion molecules, or synthesis of nitric oxide are indistinguishable responses of both IL-1 and TLR ligands. Both families nonspecifically affect antigen recognition and lymphocyte function. IL-1β is the most studied member of the IL-1 Family because of its role in mediating autoinflammatory diseases. Although the TLR and IL-1 families evolved to assist in host defense against infection, unlike the TLR Family, the IL-1 Family also includes members that suppress inflammation, both specifically within the IL-1 Family but also nonspecifically for TLR ligands and the innate immune response.
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Interleukin 1 homologues il 1f7b and il 18 contain functional mrna instability elements within the coding region responsive to lipopolysaccharide
Biochemical Journal, 2004Co-Authors: Philip Bufler, Fabia Gambonirobertson, Tania Azam, Soohyun Kim, Charles A DinarelloAbstract:IL-1F7b, a novel homologue of the IL-1 (Interleukin 1) Family, was discovered by computational cloning. We demonstrated that IL-1F7b shares critical amino acid residues with IL-18 and binds to the IL-18-binding protein enhancing its ability to inhibit IL-18-induced interferon-γ. We also showed that low levels of IL-1F7b are constitutively present intracellularly in human blood monocytes. In this study, we demonstrate that similar to IL-18, both mRNA and intracellular protein expression of IL-1F7b are up-regulated by LPS (lipopolysaccharide) in human monocytes. In stable transfectants of murine RAW264.7 macrophage cells, there was no IL-1F7b protein expression despite a highly active CMV promoter. We found that IL-1F7b-specific mRNA was rapidly degraded in transfected cells, via a 3′-UTR (untranslated region)-independent control of IL-1F7b transcript stability. After LPS stimulation, there was a rapid transient increase in IL-1F7b-specific mRNA and concomitant protein levels. Using sequence alignment, we found a conserved ten-nucleotide homology box within the open reading frame of IL-F7b, which is flanking the coding region instability elements of some selective genes. In-frame deletion of downstream exon 5 from the full-length IL-1F7b cDNA markedly increased the levels of IL-1F7b mRNA. A similar coding region element is located in IL-18. When transfected into RAW264.7 macrophages, IL-18 mRNA was also unstable unless treated with LPS. These results indicate that both IL-1F7b and IL-18 mRNA contain functional instability determinants within their coding region, which influence mRNA decay as a novel mechanism to regulate the expression of IL-1 Family members.
Diana Boraschi - One of the best experts on this subject based on the ideXlab platform.
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cytokines and soluble receptors of the Interleukin 1 Family in schnitzler syndrome
Scandinavian Journal of Rheumatology, 2019Co-Authors: Paola Migliorini, Paola Italiani, Federico Pratesi, Ilaria Puxeddu, Diana BoraschiAbstract:Objectives: Schnitzler syndrome (SchS) is an autoinflammatory disorder characterized by chronic urticaria, fever, and monoclonal gammopathy. The success of Interleukin-1 (IL-1) blocking therapies suggests a crucial role for IL-1 in disease induction. The aim of this study is to perform a comprehensive analysis of IL-1 Family cytokines and soluble receptors in a group of SchS patients.Method: Three patients fulfilling the criteria for the diagnosis of SchS were recruited; 80 blood donors formed the control group. IL-1 Family cytokines (IL-1α, IL-1β, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, sIL-1R4), and antagonists [IL-1Ra, IL-18 binding protein (IL-18BP)] were measured by a multiarray enzyme-linked immunosorbent assay. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Cytokine levels were compared by the Mann–Whitney test.Results: IL-18 and free IL-18 were increased in patients compared with controls (p = 0.005 and p = 0.0082, respectively), while IL-18BP level...
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evaluating the levels of Interleukin 1 Family cytokines in sporadic amyotrophic lateral sclerosis
Journal of Neuroinflammation, 2014Co-Authors: Paola Italiani, Paola Migliorini, Ilaria Puxeddu, Cecilia Carlesi, Paola Giungato, Barbara Borroni, Paola Bossu, Gabriele Siciliano, Diana BoraschiAbstract:Background: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to the death of affected individuals within years. The involvement of inflammation in the pathogenesis of neurodegenerative diseases, including ALS, is increasingly recognized but still not well understood. The aim of this study is to evaluate the levels of inflammation-related IL-1 Family cytokines (IL-1β, IL-18, IL-33, IL-37) and their endogenous inhibitors (IL-1Ra, sIL-1R2, IL-18BP, sIL-1R4) in patients with sporadic ALS (sALS), Methods: Sera were collected from 144 patients (125 patients were characterized by disease form, duration, and disability, using the revised ALS functional rating scale (ALSFRS-R) and from 40 matched controls. Cerebrospinal fluid (CSF) was collected from 54 patients with sALS and 65 patients with other non-infectious non-oncogenic diseases as controls. Cytokines and inhibitors were measured by commercial ELISA. Results: Among the IL-1 Family cytokines tested total IL-18, its endogenous inhibitor IL-18BP, and the active form of the cytokine (free IL-18) were significantly higher in the sALS sera than in controls. No correlation between these soluble mediators and different clinical forms of sALS or the clinical setting of the disease was found. IL-18BP was the only mediator detectable in the CSF of patients. Conclusions: Among the IL-1 Family cytokines, only IL-18 correlates with this disease and may therefore have a pathological role in sALS. The increase of total IL-18 suggests the activation of IL-18-cleaving inflammasome. Whether IL-18 upregulation in circulation of sALS patients is a consequence of inflammation or one of the causes of the pathology still needs to be addressed.
Antonin Fassmann - One of the best experts on this subject based on the ideXlab platform.
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association study of Interleukin 1 Family Interleukin 6 and its receptor gene polymorphisms in patients with recurrent aphthous stomatitis
Journal of Oral Pathology & Medicine, 2017Co-Authors: Lydie Izakovicova Holla, Simona Valova, Petra Borilova Linhartova, Jirina Bartova, Jitka Petanova, Pavel Kuklinek, Antonin FassmannAbstract:Background Recurrent aphthous stomatitis (RAS) is one of the most common oral chronic ulcerative disease in which proinflammatory cytokines such as Interleukin 1 (IL-1) and Interleukin 6 (IL-6) are thought to play an important role. The aim of this study was to investigate the possible association between polymorphisms in the IL-1 cytokine Family, IL-6 or its receptor and RAS in the Czech population. Methods A total of 248 subjects, 184 healthy controls and 64 patients with RAS were genotyped for IL-1A-889C>T, IL-1B-511C>T, IL-1B+3953C>T, IL-1RN86 bp variable number of tandem repeats (VNTR) in intron 2, IL-6-597G>A, IL-6-572G>C, IL-6-174G>C and IL-6R+48992A>C by polymerase chain reaction (PCR) methods. Results No significant differences between investigated polymorphisms in healthy subjects and patients with RAS were detected (P>0.05). In addition, complex analysis also revealed similar IL-1 or IL-6 haplotype frequencies between both groups (P>0.05). Conclusions In conclusion, IL-1 and IL-6 or its receptor gene variants cannot be used as markers for identification of Czech patients with increased risk of recurrent aphthous stomatitis.
Paola Migliorini - One of the best experts on this subject based on the ideXlab platform.
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cytokines and soluble receptors of the Interleukin 1 Family in schnitzler syndrome
Scandinavian Journal of Rheumatology, 2019Co-Authors: Paola Migliorini, Paola Italiani, Federico Pratesi, Ilaria Puxeddu, Diana BoraschiAbstract:Objectives: Schnitzler syndrome (SchS) is an autoinflammatory disorder characterized by chronic urticaria, fever, and monoclonal gammopathy. The success of Interleukin-1 (IL-1) blocking therapies suggests a crucial role for IL-1 in disease induction. The aim of this study is to perform a comprehensive analysis of IL-1 Family cytokines and soluble receptors in a group of SchS patients.Method: Three patients fulfilling the criteria for the diagnosis of SchS were recruited; 80 blood donors formed the control group. IL-1 Family cytokines (IL-1α, IL-1β, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, sIL-1R4), and antagonists [IL-1Ra, IL-18 binding protein (IL-18BP)] were measured by a multiarray enzyme-linked immunosorbent assay. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Cytokine levels were compared by the Mann–Whitney test.Results: IL-18 and free IL-18 were increased in patients compared with controls (p = 0.005 and p = 0.0082, respectively), while IL-18BP level...
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evaluating the levels of Interleukin 1 Family cytokines in sporadic amyotrophic lateral sclerosis
Journal of Neuroinflammation, 2014Co-Authors: Paola Italiani, Paola Migliorini, Ilaria Puxeddu, Cecilia Carlesi, Paola Giungato, Barbara Borroni, Paola Bossu, Gabriele Siciliano, Diana BoraschiAbstract:Background: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to the death of affected individuals within years. The involvement of inflammation in the pathogenesis of neurodegenerative diseases, including ALS, is increasingly recognized but still not well understood. The aim of this study is to evaluate the levels of inflammation-related IL-1 Family cytokines (IL-1β, IL-18, IL-33, IL-37) and their endogenous inhibitors (IL-1Ra, sIL-1R2, IL-18BP, sIL-1R4) in patients with sporadic ALS (sALS), Methods: Sera were collected from 144 patients (125 patients were characterized by disease form, duration, and disability, using the revised ALS functional rating scale (ALSFRS-R) and from 40 matched controls. Cerebrospinal fluid (CSF) was collected from 54 patients with sALS and 65 patients with other non-infectious non-oncogenic diseases as controls. Cytokines and inhibitors were measured by commercial ELISA. Results: Among the IL-1 Family cytokines tested total IL-18, its endogenous inhibitor IL-18BP, and the active form of the cytokine (free IL-18) were significantly higher in the sALS sera than in controls. No correlation between these soluble mediators and different clinical forms of sALS or the clinical setting of the disease was found. IL-18BP was the only mediator detectable in the CSF of patients. Conclusions: Among the IL-1 Family cytokines, only IL-18 correlates with this disease and may therefore have a pathological role in sALS. The increase of total IL-18 suggests the activation of IL-18-cleaving inflammasome. Whether IL-18 upregulation in circulation of sALS patients is a consequence of inflammation or one of the causes of the pathology still needs to be addressed.
Paola Italiani - One of the best experts on this subject based on the ideXlab platform.
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cytokines and soluble receptors of the Interleukin 1 Family in schnitzler syndrome
Scandinavian Journal of Rheumatology, 2019Co-Authors: Paola Migliorini, Paola Italiani, Federico Pratesi, Ilaria Puxeddu, Diana BoraschiAbstract:Objectives: Schnitzler syndrome (SchS) is an autoinflammatory disorder characterized by chronic urticaria, fever, and monoclonal gammopathy. The success of Interleukin-1 (IL-1) blocking therapies suggests a crucial role for IL-1 in disease induction. The aim of this study is to perform a comprehensive analysis of IL-1 Family cytokines and soluble receptors in a group of SchS patients.Method: Three patients fulfilling the criteria for the diagnosis of SchS were recruited; 80 blood donors formed the control group. IL-1 Family cytokines (IL-1α, IL-1β, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, sIL-1R4), and antagonists [IL-1Ra, IL-18 binding protein (IL-18BP)] were measured by a multiarray enzyme-linked immunosorbent assay. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Cytokine levels were compared by the Mann–Whitney test.Results: IL-18 and free IL-18 were increased in patients compared with controls (p = 0.005 and p = 0.0082, respectively), while IL-18BP level...
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evaluating the levels of Interleukin 1 Family cytokines in sporadic amyotrophic lateral sclerosis
Journal of Neuroinflammation, 2014Co-Authors: Paola Italiani, Paola Migliorini, Ilaria Puxeddu, Cecilia Carlesi, Paola Giungato, Barbara Borroni, Paola Bossu, Gabriele Siciliano, Diana BoraschiAbstract:Background: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to the death of affected individuals within years. The involvement of inflammation in the pathogenesis of neurodegenerative diseases, including ALS, is increasingly recognized but still not well understood. The aim of this study is to evaluate the levels of inflammation-related IL-1 Family cytokines (IL-1β, IL-18, IL-33, IL-37) and their endogenous inhibitors (IL-1Ra, sIL-1R2, IL-18BP, sIL-1R4) in patients with sporadic ALS (sALS), Methods: Sera were collected from 144 patients (125 patients were characterized by disease form, duration, and disability, using the revised ALS functional rating scale (ALSFRS-R) and from 40 matched controls. Cerebrospinal fluid (CSF) was collected from 54 patients with sALS and 65 patients with other non-infectious non-oncogenic diseases as controls. Cytokines and inhibitors were measured by commercial ELISA. Results: Among the IL-1 Family cytokines tested total IL-18, its endogenous inhibitor IL-18BP, and the active form of the cytokine (free IL-18) were significantly higher in the sALS sera than in controls. No correlation between these soluble mediators and different clinical forms of sALS or the clinical setting of the disease was found. IL-18BP was the only mediator detectable in the CSF of patients. Conclusions: Among the IL-1 Family cytokines, only IL-18 correlates with this disease and may therefore have a pathological role in sALS. The increase of total IL-18 suggests the activation of IL-18-cleaving inflammasome. Whether IL-18 upregulation in circulation of sALS patients is a consequence of inflammation or one of the causes of the pathology still needs to be addressed.