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Blood Apr 2011More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each... (Review)
Review
More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll-IL-1-receptor domain. This domain is also present in each Toll-like receptor, the receptors that respond to microbial products and viruses. Since Toll-IL-1-receptor domains are functional for both receptor families, responses to the IL-1 family are 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 called autoinflammatory diseases. For these, neutralization of IL-1β results in a rapid and sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs whereas neutralization of IL-1β is mostly anti-inflammatory. Although some autoinflammatory diseases are due to gain-of-function mutations for caspase-1 activity, common diseases such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma also are responsive to IL-1β neutralization. This review summarizes acute and chronic inflammatory diseases that are treated by reducing IL-1β activity and proposes that disease severity is affected by the anti-inflammatory members of the IL-1 family of ligands and receptors.
Topics: Animals; Autoimmune Diseases; Disease; Humans; Inflammation; Interleukin-1; Models, Biological; Molecular Targeted Therapy; Multigene Family; Receptors, Interleukin-1; Toll-Like Receptors
PubMed: 21304099
DOI: 10.1182/blood-2010-07-273417 -
Blood Mar 1996To understand the role of the proinflammatory cytokine interleukin-1 (IL-1) in disease, investigators have studied how production of the different members of the IL-1... (Review)
Review
To understand the role of the proinflammatory cytokine interleukin-1 (IL-1) in disease, investigators have studied how production of the different members of the IL-1 family is controlled, the various biologic activities of IL-1, the distinct and various functions of the IL-1 receptor (IL-1R) family, and the complexity of intracellular signaling. Mice deficient in IL-1Beta, IL-1Beta converting enzyme, and IL-1R type I have also been studied. Humans have been injected with IL-1 (either IL-1alpha or IL-1beta) for enhancing bone marrow recovery and for cancer treatment. The IL-1-specific receptor antagonist (IL-1Ra) has also been tested in clinical trials. The topics discussed in this review include production and activities of IL-1 and IL-1Ra molecules, the effects of IL-1 on gene expression, functions of cell-bound and soluble IL-1 receptors, the importance of the IL-1R accessory protein, newly discovered signal transduction pathways, naturally occurring cytokines limiting IL-1 production or activity, the effects of blocking cyclooxygenase and nitric oxide, and the outcomes of IL-1 and IL-1 Ra in human trials. Special attention is paid to IL-1beta converting enzyme and programmed cell death. The roles of IL-1 in hematopoiesis, leukemia, atherosclerosis, and growth of solid tumors are also discussed. This is a lengthy review, with 586 citations chosen to illustrate specific areas of interest rather than a compendium of references. At the end of each section, a short commentary summarizes what the author considers established or controversial topics linking the biology of IL-1 to mechanisms of disease.
Topics: Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Caenorhabditis elegans; Caspase 1; Clinical Trials as Topic; Cyclooxygenase Inhibitors; Cysteine Endopeptidases; Cytokines; Female; Gene Expression Regulation; Helminth Proteins; Hematopoiesis; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Male; Mice; Middle Aged; Neoplasms; Rats; Receptors, Interleukin-1; Sialoglycoproteins; Signal Transduction
PubMed: 8630372
DOI: No ID Found -
The Journal of Clinical Investigation Jan 2021IL-36 is a member of the IL-1 superfamily and consists of three agonists and one receptor antagonist (IL-36Ra). The three endogenous agonists, IL-36α, -β, and -γ, act... (Review)
Review
IL-36 is a member of the IL-1 superfamily and consists of three agonists and one receptor antagonist (IL-36Ra). The three endogenous agonists, IL-36α, -β, and -γ, act primarily as proinflammatory cytokines, and their signaling through the IL-36 receptor (IL-36R) promotes immune cell infiltration and secretion of inflammatory and chemotactic molecules. However, IL-36 signaling also fosters secretion of profibrotic soluble mediators, suggesting a role in fibrotic disorders. IL-36 isoforms and IL-36 have been implicated in inflammatory diseases including psoriasis, arthritis, inflammatory bowel diseases, and allergic rhinitis. Moreover, IL-36 has been connected to fibrotic disorders affecting the kidney, lung, and intestines. This review summarizes the expression, cellular source, and function of IL-36 in inflammation and fibrosis in various organs, and proposes that IL-36 modulation may prove valuable in preventing or treating inflammatory and fibrotic diseases and may reveal a mechanistic link between inflammation and fibrosis.
Topics: Animals; Fibrosis; Gene Expression Regulation; Humans; Interleukin-1; Organ Specificity
PubMed: 33463541
DOI: 10.1172/JCI144336 -
CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.Nature Medicine Jun 2018Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL) ....
Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL) . Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells), the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6). CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2-3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions.
Topics: Animals; Cytokines; Humans; Immunotherapy, Adoptive; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Macrophages; Mice; Myeloid Cells; Neoplasms; Syndrome
PubMed: 29808005
DOI: 10.1038/s41591-018-0041-7 -
Archivum Immunologiae Et Therapiae... Dec 2019This paper presents the current knowledge concerning the role of polymorphisms of IL1A and IL1B genes in periodontitis. Attention has been paid to the role of IL-1 in... (Review)
Review
This paper presents the current knowledge concerning the role of polymorphisms of IL1A and IL1B genes in periodontitis. Attention has been paid to the role of IL-1 in the pathogenesis of the disease, and to the significance of a genetic test, investigating the presence of composite two polymorphisms of IL-1 gene, as a risk factor for severe periodontitis. The significance of this test for prevention of periodontitis and its therapy has been discussed. IL-1 polymorphisms have been presented and described according to the reference single nucleotide polymorphism (SNP) identification number (rsID), established to eradicate the redundancy of reported polymorphisms in the SNP database processed by the National Center for Biotechnology Information. The prevalence of these genotypes in different populations and ethnic groups and its effect on periodontal health have been discussed. The presented data show inconsistent results. It seems that at least two polymorphisms, rs1800587 and rs1143634, are associated with periodontal inflammation. Therefore, they can be regarded as candidate genes involved in further periodontitis risk assessment. It seems that geographical and ethnical factors can play a great role, as the prevalence of specific polymorphisms varies greatly depending on the population studied.
Topics: Animals; Ethnicity; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-1; Periodontitis; Poland; Polymorphism, Genetic; Prevalence; Risk
PubMed: 31324923
DOI: 10.1007/s00005-019-00555-4 -
Cancer Cell Aug 2021Interleukin-1 (IL-1) is a key orchestrator of inflammation and plays an important role in tumor progression. Based on preclinical models and human genetic associations,... (Review)
Review
Interleukin-1 (IL-1) is a key orchestrator of inflammation and plays an important role in tumor progression. Based on preclinical models and human genetic associations, we surmise that targeting IL-1 should be considered in treating selected human tumors as well as in a prevention and/or interception setting.
Topics: Antibodies, Monoclonal, Humanized; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Lung Neoplasms; Molecular Targeted Therapy; Neoplasms; Tumor Microenvironment
PubMed: 33989512
DOI: 10.1016/j.ccell.2021.04.011 -
MBio Dec 2021Interleukin-1 (IL-1) is a key player in the immune response to pathogens due to its role in promoting inflammation and recruiting immune cells to the site of infection.... (Review)
Review
Interleukin-1 (IL-1) is a key player in the immune response to pathogens due to its role in promoting inflammation and recruiting immune cells to the site of infection. In tuberculosis (TB), tight regulation of IL-1 responses is critical to ensure host resistance to infection while preventing immune pathology. In the mouse model of Mycobacterium tuberculosis infection, both IL-1 absence and overproduction result in exacerbated disease and mortality. In humans, several polymorphisms in the gene have been associated with increased susceptibility to TB. Importantly, M. tuberculosis itself has evolved several strategies to manipulate and regulate host IL-1 responses for its own benefit. Given all this, IL-1 appears as a promising target for host-directed therapies in TB. However, for that to succeed, more detailed knowledge on the biology and mechanisms of action of IL-1 , together with a deep understanding of how host-M. tuberculosis interactions modulate IL-1, is required. Here, we discuss the most recent advances in the biology and therapeutic potential of IL-1 in TB as well as the outstanding questions that remain to be answered.
Topics: Animals; Antitubercular Agents; Genetic Predisposition to Disease; Humans; Interleukin-1; Mycobacterium tuberculosis; Polymorphism, Genetic; Tuberculosis
PubMed: 34809460
DOI: 10.1128/mBio.03134-21 -
Blood Apr 1991The polypeptide cytokine interleukin-1 (IL-1) affects nearly every tissue and organ system. IL-1 is the prototype of the pro-inflammatory cytokines in that it induces... (Review)
Review
The polypeptide cytokine interleukin-1 (IL-1) affects nearly every tissue and organ system. IL-1 is the prototype of the pro-inflammatory cytokines in that it induces the expression of a variety of genes and the synthesis of several proteins that, in turn, induce acute and chronic inflammatory changes. IL-1 is also the prototypic "alarm" cytokine in that it brings about increases in a variety of defense mechanisms, particularly immunologic and hematologic responses. Most studies on the biology of IL-1 have been performed in animals, but human subjects have recently been injected with recombinant IL-1 and the results confirm the two fundamental properties of IL-1 as being both a mediator of disease as well as of host defense. However, in either situation, over or continued production of IL-1 leads to debilitation of normal host functions; therefore, reduction of IL-1 synthesis or its effects becomes a target of therapy in many diseases. In this review, the structure, gene expression, synthesis, and secretion of IL-1 are described. In addition, the two IL-1 surface receptors, possible signal transduction mechanisms, various biologic activities, and production of IL-1 during disease states are discussed. Similarities and differences between IL-1, tumor necrosis factor, and IL-6 are presented. Although various agents for reducing the synthesis and/or for antagonizing the effects of IL-1 have been proposed, the recent cloning of a naturally occurring IL-1 receptor antagonist (IL-1ra) has opened new experimental and clinical approaches. The ability of this IL-1ra to block the triggering of IL-1 receptors in animals without agonist effects has reduced the severity of diseases such as hemodynamic shock, lethal sepsis, inflammatory bowel disease, experimental arthritis, and the spontaneous proliferation of human leukemic cells.
Topics: Amino Acid Sequence; Animals; Humans; Interleukin-1; Molecular Sequence Data; Protein Biosynthesis; Receptors, Immunologic; Receptors, Interleukin-1; Transcription, Genetic
PubMed: 1826616
DOI: No ID Found -
Frontiers in Immunology 2021Systemic sclerosis (SSc) is rare, severe connective tissue disease characterized by endothelial and vascular damage, immune activation, and resulting in inflammation and... (Review)
Review
Systemic sclerosis (SSc) is rare, severe connective tissue disease characterized by endothelial and vascular damage, immune activation, and resulting in inflammation and fibrosis of skin and internal organs, including the heart. SSc is associated with high morbidity and mortality. Cardiac involvement is frequent in SSc patients, even though often asymptomatic at early stages, and represents one of the major causes of SSc-related mortality. Heart involvement has a variable clinical presentation, and its pathogenesis is not completely understood. Myocardial fibrosis is traditionally considered the immunopathologic hallmark of heart involvement in SSc. This unique histological feature is paralleled by distinctive clinical and prognostic features. The so-called "vascular hypothesis" represents the most credited hypothesis to explain myocardial fibrosis. More recently, the prominent role of an inflammatory myocardial process has been identified as a cardinal event in the evolution to fibrosis, thus also delineating an "inflammation-driven pathway to fibrosis". The pro-inflammatory cytokine interleukin (IL)-1 has an apical and cardinal role in the myocardial inflammatory cascade and in cardiac dysfunction. The primary aim of this perspective article is: to present the emerging evidence on the role of IL-1 and inflammasome in both SSc and heart inflammation, to review the complex interplay between cellular metabolism and inflammasome activation, and to discuss the rationale for targeted inhibition of IL-1 for the treatment of SSc-heart involvement, providing preliminary experimental and clinical data to support this hypothesis.
Topics: Cytokines; Disease Management; Disease Susceptibility; Energy Metabolism; Heart Diseases; Humans; Inflammasomes; Inflammation; Inflammation Mediators; Interleukin-1; Molecular Targeted Therapy; Scleroderma, Systemic; Signal Transduction
PubMed: 33833766
DOI: 10.3389/fimmu.2021.653950 -
European Heart Journal. Cardiovascular... Jan 2018Pericarditis is a debilitating condition that results from profound inflammation of the pericardial tissue. Between 10 and 15% of first episodes of acute pericarditis... (Review)
Review
Pericarditis is a debilitating condition that results from profound inflammation of the pericardial tissue. Between 10 and 15% of first episodes of acute pericarditis will be followed by several episodes refractory to conventional treatment. Current standard of care for pericarditis treatment includes high-dose non-steroidal anti-inflammatory drugs, colchicine, and systemic corticosteroids, each associated with potentially severe toxicities and nominal efficacy. Interleukin-1 (IL-1), an apical pro-inflammatory cytokine, plays an important role as an autocrine magnifier of systemic inflammation in pericarditis. Interruption of the IL-1 circuit has been shown to have a favourable risk profile in several disease states. In this review, we discuss the growing body of evidence which supports the use of IL-1 blockade in the treatment of recurrent pericarditis as well as provide practical considerations for the use of IL-1 blockade in clinical practice.
Topics: Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Pericarditis
PubMed: 28633474
DOI: 10.1093/ehjcvp/pvx018