Is Interleukin-1 Research Articles

The Association of Interleukin 1 Beta in Recurrent Aphthous Stomatitis – A Systematic Review

Background: Recurrent aphthous stomatitis (RAS) is a chronic ulcerative disease with a complex aetiology and a strong immunological basis. The prototypical pro-inflammatory cytokine is interleukin-1 (IL-1). IL-1alpha and IL-1beta are the two subtypes of IL-1. The proinflammatory cytokine interleukin-1beta is a key mediator of inflammation which affects cell proliferation and differentiation.
 Aim: To systematically review the association of Interleukin 1 beta with the recurrent aphthous stomatitis.
 Methods: A comprehensive search was done using electronic data bases such as PubMed Central, Google Scholar and direct web search. The title scan was used to find relevant articles, which were then read and appraised for inclusion. This review analysed all research that investigated the use of IL1 beta with RAS.
 Results: Electronic database search identified 31 articles. After evaluating the title, abstract, and full text of these articles, only 2 were selected for the present systematic review. A final of 2 studies were included based on the inclusion criteria to meet the research question.
 Conclusion: This current study shows that IL1 beta is not a significant reliable indication of RAS. The association of IL1 beta and RAS varies due to a variety of confounding variables.

Changes in the Levels of Pro-Inflammatory Cytokines in Patients with Generalized Periodontitis and Hypertension, Depending on the Method of Treatment

Inflammatory mediators have an important role in the pathogenesis of periodontal disease. One of the leading mediators of the initiation of the pathological process is interleukin-1 (IL-1) – an endogenous pyrogen, a lymphocyte-activating factor. Numerous pro-inflammatory effects of interleukin-1β (IL-1β) occur in synergy with tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), effects on hematopoiesis, participates in nonspecific anti-infective defense.The objective of the study is to determine levels of interleukin-6 and tumor necrosis factor alpha (TNF-α) in patients with hypertension II stage and generalized periodontitis of the II degree depending on the treatment method.There were examined 30 patients with hypertension of the II stage and with generalized periodontitis of the II degree. Patients’ age ranged from 35 to 54 years. These patients were divided into two groups. The control group included 10 patients without general somatic pathology and with healthy periodontitis of the same age. The result of the analysis of tumor necrosis factor alpha (TNF-α) in patients in the first group before the treatment was 10.69±2.33 pg/ml. After the treatment this indicator was 6.97±1.57 pg/ml (p>0.1) in patients of the first group.In patients of the second group the tumor necrosis factor alpha (TNF-α) was 9.49±2.2 pg/ml; after the treatment according to the offered scheme this figure decreased up to 2.77±0.9 pg/ml (p<0.01). The level of tumor necrosis factor alpha (TNF-α) in the control group was 1.5±0.77 pg/ml.Interleukin-6 was 9.91±2.04 pg/ml before the treatment in the first group. After the treatment according to the standard scheme, the level of interleukin-6 was 6.33±0.97 pg/ml (p>0.1). In the second group, before the treatment the level of interleukin-6 was 9.65±2.41 pg/ml; after the treatment according to the offered scheme it was 2.62±0.5 pg/ml (p<0.01). In the control group the interleukin-6 level was 2.24±0.51 pg/ml.Analyzing the obtained results after the treatment in both groups we can conclude: after the treatment of generalized periodontitis of the II degree in patients with hypertension of the II stage, indices of pro-inflammatory cytokines decreased and ranged in normal limits; in patients from the second group (who received the offered scheme of treatment -including medicines) indexes of pro-inflammatory cytokines were significantly lower than in patients with the standard treatment scheme; the proposed scheme of treatment is more effective for treatment patients with generalized periodontitis of the II degree and hypertension of the II stage.

Étude des polymorphismes des gènes de l’interleukine-1 et de l’antagoniste du récepteur de l’interleukine-1 chez des patients atteints de polyarthrite rhumatoïde

ObjectivesOne of the most important pro-inflammatory cytokines in the pathophysiology of rheumatoid arthritis (RA) is interleukin 1 (IL-1). The purpose of this study is to evaluate the association between IL-1B (-511), IL-1 (+3953), IL-1 RN variable number of tandem repeat (VNTR) polymorphisms and the occurrence in Algerian patients with rheumatoid arthritis. We also analyze their correlations with clinical and biological phenotypes. Patients and methodsOne hundred and forty-seven patients with RA (119 women, 28 men) and 127 controls (70 women, 57 men) were included in the study. The analysis of two polymorphisms of IL-1B-511 and IL-1B+3953 was done by PCR-RFLP. Analysis of IL1-RN VNTR polymorphism was performed by PCR. ResultsNo significant difference in genotype, allelic and haplotype distribution at the three polymorphisms was observed between RA patients and controls. However, the genotype (T/T) polymorphism of IL-1B-511 is more frequent in the group of patients with positive ACPA compared with negative ACPA group (Pc=0.01, OR=4.65). Moreover, we noted that the haplotype (IL-1RN* 1/IL-1B-511T/IL-1B+3953C) was more frequent (Pc=0.03, OR=2.05) in the positive ACPA group. ConclusionThe association between the allele 1 of IL-1 RN VNTR, T allele of IL1B-511 and C allele of IL1-B +3953 polymorphisms seems to predispose to the synthesis of ACPA and therefore to the occurrence of ACPA positive RA. Further studies with a larger number of patients are needed to define the real role of IL-1 in the susceptibility to or severity of RA.

4′-Chlorodiazepam — Agonist of peripheral benzodiazepine receptors as a protecting factor in IL-1 induced deregulation of collagen biosynthesis in cultured human chondrocytes

Degenerative joint diseases are related to the excessive degradation of collagen and proteoglycans in cartilage. One of the potent inflammatory mediators of cartilage metabolism is interleukin-1 (IL-1) that has been implicated in the pathogenesis of degenerative joint diseases. Peripheral benzodiazepine receptor ligands have anti-inflammatory activity in rheumatoid arthritis. The present study shows that 4′-chlorodiazepam (Ro-54864), an agonist of peripheral benzodiazepine receptors, counteract inhibition of collagen and DNA biosynthesis, induced by IL-1. Pk-1195, an antagonist of peripheral benzodiazepine receptors did not restore inhibitory effects of IL-1. The mechanism of collagen biosynthesis and cell division regulation involves insulin-like growth factor-I receptor signaling. We found that IL-1 inhibited expression of IGF-IR, while Ro-54864 stimulated the expression of this receptor. Increase in the expression of this receptor was accompanied by increase in mTOR expression and AKT phosphorylation while it had no effect on Ras–Raf–mitogen activated protein kinase (MAPK) pathway. Although IL-1 caused activation of apoptosis in chondrocytes, an addition of Ro-54864 to the cells inhibited the process as detected by annexin V cell staining followed by flow cytometry. The mechanism of this process may be related to protective effect of signal induced by IGF-I receptor. The data suggest that the mechanism of the protective effects of Ro-54864 on IL-1-induced effects in chondrocytes undergoes through mTOR and AKT signaling. It suggest that peripheral benzodiazepine receptor agonist may be considered as a potential pharmacotherapeutical agents in the treatment of inflammatory diseases.

Infection as a stressor: a cytokine-mediated activation of the hypothalamo-pituitary-adrenal axis?

Infections are associated with increased plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone. Hypothalamo-pituitary-adrenal (HPA) responses have also been observed with immunological stimuli that are not infective. Although such responses have been suggested to be mediated by ACTH secreted by lymphocytes, adrenocortical activation by immunological stimuli requires a functional pituitary. The most likely mechanism by which immunological stimuli activate the HPA axis involves production of cytokines by lymphocytes. The prime candidate is interleukin 1 (IL-1), because IL-1 production follows activation of the immune system and IL-1 administration is a potent activator of the HPA axis. However, other cytokines, such as tumour necrosis factor, may also be involved. Most immunological stimuli and IL-1 also activate both peripheral and central noradrenergic neurons. IL-1-induced activation of the HPA axis in vivo depends upon secretion of corticotropin-releasing factor (CRF), an intact pituitary, and the ventral noradrenergic bundle which innervates the CRF-containing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Besides elevating body temperature, administration of IL-1 elicits a number of behavioural responses in rats and mice, including anorexia, increased sleep time, decreased investigation of novel objects and other animals, increased defensive withdrawal and other behaviours characteristic of sickness. Some of these responses can be reversed by CRF-antagonists and mimicked by CRF administration. Thus, endogenous production of IL-1 can account for a range of physiological and behavioural responses characteristic of sickness. Nevertheless, definitive evidence that IL-1 mediates these responses in sick animals is lacking.

Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment

The tumor microenvironment consists of tumor, immune, stromal, and inflammatory cells which produce cytokines, growth factors, and adhesion molecules that promote tumor progression and metastasis. Of particular interest in this setting is interleukin-1 (IL-1), a pleiotropic cytokine with numerous roles in both physiological and pathological states. It is known to be up regulated in many tumor types and has been implicated as a factor in tumor progression via the expression of metastatic and angiogenic genes and growth factors. A number of studies have reported that high IL-1 concentrations within the tumor microenvironment are associated with a more virulent tumor phenotype. Solid tumors in which IL-1 has been shown to be up regulated include breast, colon, lung, head and neck cancers, and melanomas, and patients with IL-1 producing tumors have generally bad prognoses. The exact mechanisms by which IL-1 promotes tumor growth remain unclear, though the protein is believed to act via induction of pro-metastatic genes such as matrix metalloproteinases and through the stimulation of adjacent cells to produce angiogenic proteins and growth factors such as VEGF, IL-8, IL-6, TNFα, and TGFβ. The IL-1 receptor antagonist (IL-1ra) is a naturally occurring inhibitor to IL-1 and acts by binding to the IL-1 receptor without activating it. The protein has been shown to decrease tumor growth, angiogenesis, and metastases in murine xenograft models. Our focus in this review is to summarize the known data on the role of IL-1 in tumor progression and metastasis and the use of IL-1 inhibition as a novel therapeutic approach in the treatment of solid organ malignancies.

The Inhibitory Effect of Metronidazole and Doxycycline-HCl on proMMP-3 Production in Gingival Fibroblast

Matrix metalloproteinases(MMP) are a family of proteolytic enzymes that mediate the degradation of extracellular matrix macromolecules, including interstitial and basement membrane collagens, fibronectin, laminin, and proteoglycan core protein. The major cell types(fibroblasts, keratinocytes, endothelial cells, and macrophages) in periodontal tissue are capable of responding to growth factors and cytokines, as well as to products released from the microbial flora by induction of transcription of one or more MMP genes1). These MMPs share some common properties: 1) secretion from the cell in a latent form(proenzyme) with its subsequent activation in the extracellualr space; 2) containing zinc cation at the active site; 3) inhibition by chelators of calcium(e.g., EDTA), and zinc(e.g., 1, 10 phenanthroline); 4) inhibition by tissue inhibitors of metalloproteinases(TIMP); and 5) degrading at least one component of the extracellular matrix(e.g., collagen)2). One prominent member of these MMPs, MMP-3(stromelysin-1) is capable of degrading the numerous extracellular matrix macromolecules(ECM) including fibronectin, laminin, proteoglycan core protein, collagen IV, V, IX, X, and elastin3). Increase of MMP-3 activity associated with several chronic inflammatory disease appear to be the result of specific inductive mechanisms. One of the mediators in induction of MMP-3 is interleukin-1(IL-1), cell product that has important regulatory functions mediating the body's response to microbial invasion, inflammation, and tissue injury4,5,6,7). Especially, IL-1 is thought to play a important role in the tissue destruction associated with inflammatory diseases such as rheumatoid arthritis and periodontal disease8,9). As periodontitis is specifically associated with the destruction of periodontal connective tissues, it is closely related to both IL-1 and MMPs. Gingivitis can trigger the initial cascade of periodontal destruction. The human gingival fibroblast is prominent cell type in the gingival connective tissue and products cytokines inducted by microbial infection in periodontal disease. In the periodontal disease, the upregulation of MMP expression in response to locally released IL-1 may provide one component of this pathologic process. IL-1 has been identified in both the gingiva and gingival crevicular fluids of periodontitis patients10,11). In Vitro, fibrob-

Effect of age on fever response to recombinant interleukin-6 in a murine model.

A blunted or absent fever response to infection may occur in elderly people. Fever is mediated by endogenously produced molecules of leukocytes. The best studied of these molecules is interleukin-1 (IL-1). However, interleukin-6 (IL-6) is also known to possess the biological properties of pyrogenic cytokines. In this study, we assessed the influence of age on the febrile response to recombinant IL-6 (rIL-6) using a well-defined murine model. Balb/c male mice were injected intravenously and intraperitoneally with varying doses of rIL-6. Control mice received pyrogen-free phosphate buffered saline. Temperatures were measured rectally at baseline and at 10-minute intervals for 120 minutes post-injection using a thermistor probe. Stable baseline temperatures were first determined, and post-injection temperatures were recorded every 10 minutes for up to 120 minutes. A dose-response correlation was found between the amount of the injected rIL-6 and the mean temperature changes in both young and old mice. The mean temperature changes for both young and old mice were higher following a 25 ng dose compared to a 12.5 ng dose of rIL-6 injected intravenously, and, likewise, following a 500 ng dose compared to a 250 ng dose of rIL-6 injected intraperitoneally. A significant delay in the peak temperature response was seen for both young and old mice when comparing intraperitoneal injections to intravenous injections. However, control mice showed no changes. Our findings confirm that IL-6 has a role in the pathogenesis of fever and that aging alters the febrile response to rIL-6.

Interleukin 1 receptors in the brain and endocrine tissues

Immune activation is often accompanied by profound alterations in neurological and endocrine function, such as fever, increased somnolence, decreased appetite, activation of the hypothalamic—pituitary—adrenal axis, and suppression of the hypothalamic—pituitary—adrenal hypothalamic—pituitary—thyroid axes. These well-recognized systemic responses to injury and infection have been attributed to circulating pro-inflammatory cytokines, the best characterized of which is interleukin 1 (IL-1). Here Emmett Cunningham and Errol De Souza discuss the mechanisms by which blood-borne IL-1 might affect such changes in the nervous and neuroendocrine systems.

The role of dendritic cells in the regulation of T cell cytokine synthesis.

Antigen presenting cells (APC) have been implicated frequently in the numerous cytokine network models, chiefly as a hypothetical source of a critical mediator that is important in induction of an immune response. The example usually quoted is interleukin 1 (IL-1) (1), even though it has been clear for some time that the most potent form of APC, the dendritic cell (DC), is an IL-1 responder rather than producer (2). Other cytokines, such as IL-6, have also been proposed as important in induction (3); but IL-6 effects are so pleiotropic that it is difficult to ascribe a specific APC related role to this cytokine (4).

Interleukin-1β decreases HLA class II expression on a glioblastoma multiforme cell line

Antigens encoded within the major histocompatibility complex (MHC) are not normally expressed in the central nervous system (CNS), but can be induced by treatment with interferon-γ (IFN-γ). Other cytokines released during an inflammatory process can potentially influence MHC expression as well. One cytokine of interest is interleukin-1 (IL-1), an immunoregulatory polypeptide that is produced by macrophages and also by cells in the CNS. In this study, the effedt of IL-1β on MHC expression in a human glioblastoma multiforme cell line, U-105 MG, has been examined. Treatment of U-105 MG with 10 U IL-1β/ml for a period of 5 days resulted in a decrease in constitutive cell surface HLA class II expression and limited the induction of class II by IFN-γ. This effect was also observed on steady-state levels of class II RNA and could be neutralized with antibodies to IL-1β. All class II transcripts examined (HLA-DR, -DQ, and -DP α and β) were affected. Class I expression was only marginally changed by IL-1β treatment. A minimal concentration of 1 U IL-1β/ml was required to reduce class II expression and a kinetics experiment indicated that U-105MG must be treated for at least 4 days with IL-1β for a decrease in class II expression to be observed. This study suggests that IL-1 may play a role in limiting immunoreactivity in the CNS by limiting class II induction.

Metabolism and β-cell function of rat pancreatic islets exposed to human interleukin-1β in the presence of a high glucose concentration

It has been postulated that one of the factors causing immune-mediated pancreatic β-cell destruction in insulin-dependent diabetes mellitus (IDDM) is interleukin-1 (IL-1). Rat pancreatic islets exposed to human recombinant IL-1β (rIL-1β) for 48 h in vitro exhibit a markedly reduced glucose-stimulated insulin secretion. Also, a deleterious effect of glucose on β-cell function, especially under conditions of a reduced β-cell mass, which may exist in the early phase of IDDM has been suggested. In this study the response of rat pancreatic islets in vitro to a combination of the cytokine and high glucose concentration have therefore been assessed. Thus, islets were cultured for 48 h at either 11.1 or 56 mM glucose with or without 25 U/ml rIL-1β. Exposure to the cytokine reduced the islet DNA content at both glucose concentrations by 20–25%. In short-term incubations in the absence of rIL-1β after the preceding culture with the cytokine, the glucose-stimulated insulin release was reduced by 70% in islets cultured at 11.1 mM glucose and by only 40% after culture at 56 mM glucose, when compared to the corresponding control islets. The utilization of D-[5- 3H]glucose, i.e., the catabolism of glucose in the glycolytic pathway, was the same in all groups of islets. However, the D-[6- 14C]glucose oxidation rate, i.e., the metabolism of glucose in the Krebs cycle, was reduced by about 65% in rIL-1β exposed islets kept at 11.1 mM glucose and 46% in islets cultured at 56 mM glucose. The islet ATP content was reduced by about 40–45% by rIL-1β at both glucose concentrations and also the ratio ATP/ADP was reduced. The rIL-1β exposed islets maintained at 11.1 mM glucose failed to increase their oxygen uptake in response to glucose, whereas 56 mM glucose cultured islets showed a similar respiratory pattern as their controls. The islets exposed to rIL-1β exhibited also a 50–60% reduction in their cAMP content. In control islets cultured at 56 mM glucose a slight decrease in their glucose oxidation rates and a lowering in the ATP/ADP ratio was recorded. Taken together the present results point towards a disturbed glucose metabolism in the mitochondria of β-cells exposed to rIL-1β. However, a high glucose concentration does not appear to further deteriorate β-cell function when present together with rIL-1β, but rather to counteract some of the effects of rIL-1β. The findings also suggest a slightly impairing effect of a very high glucose concentration on islet function, although it remains unclear if such an effect is of pathophysiological relevance.

Role of interleukin-1 in human B-cell activation.

Mononuclear phagocytes (Mo) play an essential role in both T- and B-cell activation (Unanue, 1972). Thus, Mo have a critical function both as antigen- presenting cells and as cells that provide a focus for effective B- and T-cell collaboration. In addition to activities carried out by means of direct contact between Mo and responding lymphocytes, a number of other functions of Mo appear to be accomplished by secreted factors. The best studied of these factors is Interleukin-1 (IL-1), a Mo-derived factor of 12,000–16,000 daltons that has a variety of amplifying effects both on immunological reactivity and on inflammatory responses in general (Oppenheim and Gery, 1982). While the immunoregulatory role of IL-1 has been well described in a number of murine models of T- and B-cell activation, the function of this molecule in human immune responsiveness has been less well described. The studies presented in this chapter were therefore undertaken, to examine the role of IL-1 in the regulation of antibody production in humans. Specifically, the in vitro generation of immunoglobulinsecreting cells (ISC) triggered by the T-cell-dependent polyclonal B-cell activators, pokeweed mitogen (PWM) and formalinizedStaphylococcus aureus, was used as a model system for dissecting in detail the immunomodulatory potential of IL-1. The data support the conclusion that IL-1 plays a necessary role in the generation of ISC in humans. Moreover, the results indicate that IL-1 delivers a requisite differentiation signal directly to the B-cell, without which subsequent responsiveness to T-cell-derived helper factors and maturation to Ig-secreting cells do not occur.

Mechanism of action of cyclosporin A. Effect on T-cell-binding of interleukin 1 and antagonizing effect of insulin.

Previous studies have shown that cyclosporin A (CyA) prevents the elaboration of the lymphokine leucocyte migration inhibitory factor (LIF). Since LIF production is interleukin 1 (IL-1)-dependent, we carried out experiments using partially and highly purified IL-1 preparations to study the effect of CyA. We found that (a) IL-1 was consistently depleted during a 1-h incubation with human blood T lymphocytes but not with B lymphocytes or erythrocytes; (b) the depletion could not be ascribed to pinocytosis, cell functions requiring active metabolism, or enzyme-mediated destruction of IL-1; (c) CyA, but not biologically inactive cyclosporin, antagonized the apparent absorption of IL-1; (d) T cells pre-exposed to CyA were rendered incapable of removing the monokine; and (e) CyA was capable of displacing IL-1 once absorbed by T cells. Because the putative binding of IL-1 showed saturability, reversibility (with CyA as a probe), and tissue specificity consistent with a known target for the monokine, we propose that IL-1 interacts with a receptor-like structure on T cells. Finally, we found that insulin interfered with the function of CyA at the very early macrophage-T-cell co-operative stage, even at physiological concentrations.