LECTURE SERIES - INTERLEUKIN 1 (IL1)
Interleukin-1 | IL1
IL-1α is a pro-inflammatory cytokine that affects T-helper cells causing the induction of IL-2 secretion and the expression of IL-2 receptors, as well as causing B cells to promote cell proliferation and immunoglobulin synthesis.
IL-1α is present in various biological fluids and the monitoring its levels is a valuable biomarker.
IL1a possesses a wide spectrum of metabolic, physiological, haematopoietic activities, and plays one of the central roles in the regulation of the immune responses.
Both elevations in serum levels and joint fluids (synovial fluids) are detected in rheumatoid arthritis.
Increased plasma and CSF levels are found in patients with schizophrenia.
Significantly elevated concentrations in gingival cervical fluid in subjects with peridontitis are detected.
Urinary levels of IL-1α correspond to disease and therapy response in bladder cancer.
IL-1 can be induced by a combination of other cytokines, endotoxins, viruses, mitogens and antigens. IL-1 mediates a wide variety of biological actions. It stimulates the production and secretion of IL-2 and the expression of IL-2 receptors by helper cells. IL-1 acts synergistically with other factors in the activation and differentiation of B cells. In synergy with TNFá, IL-1 activates osteoclasts and therefore plays an important role in the regulation of bone metabolism.
IL-1 has different effects on the central nervous system. It is an endogenous pyrogen and causes fever in humans at doses less than 1 ng/kg. Additionally, it induces the synthesis of ACTH, endorphins, vasopressin and somatostatin. Furthermore, it stimulates the activation and differentiation of NK cells, fibroblasts and thymocytes.
IL-1 acts anti-proliferatively on many tumor cell types, increases the tumor cytotoxicity of macrophages and induces tumor regression. Elevated serum or blood levels of IL-1α have been found in of several carcinomas such as head and neck cancer, pancreatic cancer and thyroid cancer, in experimental acute pyelonephritis, in acute viral hepatitis and in septic shock.
Interleukin-1 caused a severe reduction in cerebral blood flow and increase in infarct volume. Blockade of endothelin-1 receptors reversed this hypoperfusion, reduced tissue damage, and improved functional outcome.
J Biol Regul Homeost Agents. 2020 Mar 14;34(2):1. doi: 10.23812/CONTI-E. Online ahead of print.
Induction of Pro-Inflammatory Cytokines (IL-1 and IL-6) and Lung Inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): Anti-Inflammatory Strategies
Coronavirus-19 (COVI-19) involves humans as well as animals and may cause serious damage to the respiratory tract, including the lung: coronavirus disease (COVID-19). This pathogenic virus has been identified in swabs performed on the throat and nose of patients who suffer from or are suspected of the disease. When COVI-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6. The binding of COVI-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1β which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1β which is a mediator of lung inflammation, fever and fibrosis. Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. Cytokine IL-37 has the ability to suppress innate and acquired immune response and also has the capacity to inhibit inflammation by acting on IL-18Rα receptor. IL-37 performs its immunosuppressive activity by acting on mTOR and increasing the adenosine monophosphate (AMP) kinase. This cytokine inhibits class II histocompatibility complex (MHC) molecules and inflammation in inflammatory diseases by suppressing MyD88 and subsequently IL-1β, IL-6, TNF and CCL2. The suppression of IL-1β by IL-37 in inflammatory state induced by coronavirus-19 can have a new therapeutic effect previously unknown. Another inhibitory cytokine is IL-38, the newest cytokine of the IL-1 family members, produced by several immune cells including B cells and macrophages. IL-38 is also a suppressor cytokine which inhibits IL-1β and other pro-inflammatory IL-family members. IL-38 is a potential therapeutic cytokine which inhibits inflammation in viral infections including that caused by coronavirus-19, providing a new relevant strategy.
Adv Exp Med Biol. 2020;1240:1-23. doi: 10.1007/978-3-030-38315-2_1.
IL-1 Signaling in Tumor Microenvironment
Interleukin 1 (IL-1) has long been known for its pleiotropic effects on inflammation that plays a complex, and sometimes contrasting, role in different stages of cancer development. As a major proinflammatory cytokine, IL-1β is mainly expressed by innate immune cells. IL-1α, however, is expressed by various cell types under physiological and pathological conditions. IL-1R1 is the main receptor for both ligands and is expressed by various cell types, including innate and adaptive immune cell types, epithelial cells, endothelial cells, adipocytes, chondrocytes, fibroblasts, etc. IL-1 and IL-1R1 receptor interaction leads to a set of common signaling pathways, mainly the NF-kB and MAP kinase pathways, as a result of complex positive and negative regulations. The variety of cell types with IL-1R1 expression dictates the role of IL-1 signaling at different stages of cancer, which under certain circumstances leads to contrasting roles in tumor development. Recent availability of IL-1R1 conditional knockout mouse model has made it possible to dissect the role of IL-1/IL-1R1 signaling transduction in different cell types within the tumor microenvironment. This chapter will focus on the role of IL-1/IL-1R1 in different cell types within the tumor microenvironment and discuss the potential of targeting this pathway in cancer therapy.
A Review of Interleukin-1 in Heart Disease: Where Do We Stand Today?
Cardiol Ther 2018 Feb 7. Epub 2018 Feb 7.
Department of Cardiology, Tel Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Cardiovascular diseases are the leading cause of death worldwide. Research in the last two decades has emphasized the inflammatory process as a key component in the pathogenesis of many of them. The Interleukin-1 family is a pivotal element of inflammation and has been well studied as a therapeutic target in various inflammatory states. Recent trials have explored the effect of Interleukin-1 blockade in cardiovascular diseases and initial evidence of the relevance of such treatment in this field of medicine accumulate. This review will describe the role of Interleukin-1 in heart diseases and the potential therapeutic effect of its blockade in such diseases.
Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade.
J Neuroinflammation 2018 Feb 9;15(1):38. Epub 2018 Feb 9.
Division of Rheumatology, Department of Pediatrics, Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave, MLC 4010, Cincinnati, OH, 45229, USA.
Background: Autoinflammatory disorders are distinguished by seemingly random episodes of systemic hyperinflammation, driven in particular by IL-1.
Recent pre-clinical work has shown a key role for IL-1 in epilepsy in animal models, and therapies for autoinflammation including IL-1 blockade are proposed for refractory epilepsy.
Case Presentation: Here, we report an adolescent female with signs of persistent systemic inflammation and epilepsy unresponsive to multiple anti-epileptic drugs (AED). She was diagnosed with generalized epilepsy with a normal brain MRI and an electroencephalogram (EEG) showing occasional generalized spike and slow wave discharges. Her diagnostic evaluation showed no signs of autoimmunity or genetic causes of epilepsy or periodic fever syndromes but persistently elevated serum inflammatory markers including S100 alarmin proteins. She experienced prompt clinical response to IL-1 blockade with first anakinra and then canakinumab, with near complete resolution of clinical seizures. Additionally, she displayed marked improvements in quality of life and social/academic functioning. Baseline gene expression studies on peripheral blood mononuclear cells (PBMC) from this patient showed significantly activated gene pathways suggesting systemic immune activation, including focal adhesion, platelet activation, and Rap1 signaling, which is an upstream regulator of IL-1β production by the NLRP3 inflammasome. It also showed activation of genes that characterize inflammasome-mediated autoinflammatory disorders and no signs of interferon activation. This gene expression signature was largely extinguished after anakinra treatment.
Conclusions: Together, these findings suggest that patients with epilepsy responsive to immune modulation may have distinct autoinflammatory features supporting IL-1 blockade. As such, IL-1 blockade may be highly efficacious adjunctive medication for certain refractory epilepsy syndromes.
Study the relevance between inflammatory factors and estradiol and their association with knee osteoarthritis in postmenopausal women.
Eur Rev Med Pharmacol Sci 2018 Jan;22(2):472-478
Department of Endocrinology, Shandong Provincial Hospital Affiliated with Shandong University, Jinan, China.
Objective: To investigate whether serum levels of inflammatory factors and estradiol (E2) are involved in the pathogenesis of postmenopausal women with knee osteoarthritis (OA).
Patients And Methods: 58 randomly patients diagnosed with postmenopausal knee OA that underwent orthopedic surgery from October 2013 to October 2016 in our hospital were selected. These patients, considered as the experimental group, according to the degree of cartilage damage, were divided into light, medium and heavy groups. 58 patients with menstrual disorders without knee OA were in the control group. 35 cases without osteoarthritis were included in the normal control group. Serum levels of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), erythrocyte sedimentation rate (ESR), high sensitive C- reactive protein (CRP), estradiol (E2) and IL-1, IL-6 and TNF-α levels in the synovial fluid of the experimental group were measured.
Results: The serum levels of IL-1, IL-6, TNF-α, and CRP in the normal control group, the control group and the experimental group were gradually increasing, the difference was statistically significant (p<0.05). The level of serum E2 was gradually decreasing (p<0.05); the difference of ESR between normal control group and control group had no significant difference (p>0.05), but the level of ESR in experimental group was higher than the normal control group and the control group (p<0.05). The serum levels of IL-1, TNF-α in experimental group of mild, moderate and severe sub-group were gradually increasing, the difference was statistically significant (p<0.05); while the level of IL-6 in the early, middle stage of OA increased significantly, and the late was reduced (p<0.05). The level of E2 was gradually decreased in the mild, moderate and severe sub-group of the experimental group, which had statistically significant difference (p<0.05). The level of serum E2 in the experimental group was positively correlated with the levels of IL-1, IL-6 and TNF-α in synovial fluid (p<0.05).
Conclusions: The lack of estradiol is associated with the pathogenesis of OA in postmenopausal women, the inflammatory factors of IL-1, IL-6, TNF-α in postmenopausal increased in serum and synovial fluid may promote and aggravate the OA.