Function Of Interleukin-33 Research Articles

Interleukin-33 as a marker for disease activity in rheumatoid arthritis

Background Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder thought to be autoimmune in nature and predominately affects synovial joints. Interleukin-33 (IL-33) is a newly reported cytokine of the IL-1 family. Aim of the work The aim of this study was to assess the role of IL-33 in the pathogenesis of RA. Patients and methods Group A included 30 adult patients with RA; all cases were diagnosed according to the American College of Rheumatology criteria for RA. Group B included 20 healthy adult persons (age and sex matched) who comprised the control group. The serum IL-33 levels were examined by using the enzyme-linked immunosorbent assay for 30 patients with RA and 20 healthy individuals. Disease activity was assessed according to disease activity score 28–C-reactive protein (CRP) scale. Results IL-33 was increased in all RA patients compared with controls. IL-33 was highly correlated to erythrocyte sedimentation rate, CRP, rheumatoid factor, anti-cyclic citrullinated peptide, and disease activity score 28–CRP score. Therefore, IL-33 most probably has a significant role to play in the pathogenesis of RA. Conclusion IL-33 most probably has a significant role in the pathogenesis of RA. IL-33 serum levels paralleled the severity of the disease subset. Understanding the functions of IL-33 is important for the development of new therapeutic approaches including IL-33 inhibitors as a therapeutic target.

Mo1923 Upregulation and the Regulation of Esophageal Epithelial-Derived IL-33 in Non-Erosive Reflux Disease

Background and Aims: Interleukin-33 (IL-33) is a tissue-derived cytokine constitutively expressed in epithelial cells of tissues exposed to the environment and plays a role in sensing damage caused by inflammatory diseases. IL-33 acts as both a traditional cytokine and as a chromatin-associated nuclear factor in both innate and adaptive immunity. We recently showed that IL-33 in the esophageal mucosa is up-regulated in reflux esophagitis (J Gastroenterol, 2014). However, IL-33 expression in non-erosive reflux disease (NERD), and the regulation of cytokines by IL-33 has not been examined. We therefore examined the expression of IL-33 in NERD patients and the function of IL-33 in the production of inflammatory cytokines in esophageal epithelial cells using normal esophageal squamous epithelial cells (HEECs). Methods: The expression of IL-33 in the lower esophageal mucosa of NERD patients and controls was examined using real-time RT-PCR and immunofluorescence. Intercellular space diameter (ISD) was measured by blinded light microscopy of esophageal biopsies. Cytokines produced from an esophageal biopsy specimen were determined using the Bio-Plex suspension array system. We also developed and used an air-liquid interface (ALI) in vitro model for culture of stratified squamous epithelium using primary HEECs (Am J Physiol Gastrointest Liver Physiol. 2012). IL-33 production by the cultures was assessed by western blotting and immunofluorescence staining. Cytokines produced by the cell layers after stimulation were measured using ELISA and the Bio-Plex suspension array system. Pharmacological inhibitors were used to examine the regulation of cytokine production by IFNg, and IL-33 siRNA was used to examine its function in HEECs. Results: IL33 expression and mean ISD were significantly increased in the mucosa of the NERD group compared to that of the control group. The upregulated IL-33 expression was mainly located in the nuclei of the basal cell layer in the NERD group. The esophageal biopsy specimen produced IL-8 and IL-6. In vitro, IFNg stimulation from the basal side of the inserts induced nuclear IL-33 expression and IL-33 mRNA in a doseand time-dependent manner in ALIcultured HEECs. Furthermore, IFNg induced IL-8 and IL-6 release from the ALI-cultured HEECs. IFNg-induced IL-33 protein up-regulation in the ALI-cultured HEECs was mediated through JAK and p38MAPK activation, but not through PKA activity. IFNg-induced IL-8 and IL-6 release was JAK, p38MAPK, and STAT1 dependent. IFNg-induced IL-8 and IL-6

Dual function of IL-33 on proliferation of NIH-3T3 cells

The interleukin-33 (IL-33)-ST2L signaling pathway has been shown to play important roles in the field of immunology, especially as a trigger for allergic reactions such as bronchial asthma. However, coming back to the original finding that the ST2 gene is induced during initiation of the cell cycle of fibroblastic cell lines, the possible functions of the ST2 gene products and their specific ligand, IL-33, in the field of cell growth regulation are still interesting problems to be solved.In this study, we used NIH-3T3 mouse cell line and added IL-33 before and after cell proliferation assay, which revealed the dual function of IL-33. When IL-33 was added to the confluent cells before the start of cell proliferation, it suppressed the cell growth concentration-dependently. On the other hand, if IL-33 was added after the start of cell proliferation, it enhanced the cell growth.The negative effect of IL-33 on cell proliferation is a novel finding and would provide an important clue to the roles of IL-33 and ST2/ST2L in growth regulation.

IL-33 attenuates the development of experimental autoimmune uveitis.

Interleukin-33 (IL-33) is associated with several important immune-mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here, we investigated the function of IL-33 in the development of experimental autoimmune uveitis (EAU). IL-33 and IL-33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL-33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL-33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2-deficient mice developed exacerbated EAU compared with WT mice, and administration of IL-33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL-33-treated mice was accompanied by decreased frequency of IFN-γ+ and IL-17+ CD4+ T cells and reduced IFN-γ and IL-17 production but with increased frequency of IL-5+ and IL-4+ CD4 T cells and IL-5 production in the draining lymph node and spleen. Macrophages from the IL-33-treated mice show a significantly higher polarization toward an alternatively activated macrophage phenotype. Our results therefore demonstrate that the endogenous IL-33/ST2 pathway plays an important role in EAU, and suggest that IL-33 represents a potential option for treatment of uveitis.

Biological role of Interleukin 33 and its importance in pathophysiology of cardiovascular system

Interleukin 33 (IL-33) is a member of the IL-1 cytokin family. It is expressed by various cells and tissues, mainly epithelial and endothelial cells. It is a cytokine with dual function. It may act both as a traditional cytokine and as intracellular nuclear factor, functioning as transcription regulator. Its biological effect via interaction with membrane-bound ST2 receptor and IL-1 receptor accessory protein (IL-1RAcP) is associated with the induction of Th2-type immune response and IL-5 and IL-13 synthesis. IL-33 has a strong immunoregulatory properties. Depending on the type of activated cells, microenvironment, and costimulatory factors, IL-33 can act either as a pro- or anti-inflammatory cytokine. Recent studies indicate various protective effect of IL-33/ST2 sygnaling in atherosclerosis, obesity, disorders in glucose homeostasis and in heart diseases. The paper presents current state of knowledge about the structure and biological function of IL-33 and its receptor ST2, with particular emphasis on its role in pathophysiology of cardiovascular system.

Immune function of interleukin-33 and its relation to human diseases

Interleukin-33 (IL-33) is a novel cytokine and belongs to IL-1 family expressed in a wide range of organs and cells. IL-33 is a dual-functional molecule: as a classical cytokine it induces immune response and it also regulates gene transcription in the nucleus. Altered expression of IL-33 has been observed in various human diseases such as inflammation, autoimmune diseases, and virus infection. The article reviews advances on immune function of IL-33 and its relation to a variety of human diseases.

A8.6 Interleukin 33 skin overexpression does not induce inflammation

BackgroundThe cytokine interleukin 33 (IL-33), a member of the IL-1 family, is released in response to various types of endothelial or epithelial cell damage. IL-33 is constitutively expressed in epidermal...

Emerging role of interleukin‐33 in autoimmune diseases

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family. It predominantly induces type 2 immune responses and thus is protective against atherosclerosis and nematode infections but contributes to allergic airway inflammation. Interleukin-33 also plays a pivotal role in the development of many autoimmune diseases through mechanisms that are still not fully understood. In this review, we focus on the recent advances in understanding of the expression and function of IL-33 in some autoimmune disorders, aiming to provide insight into its potential role in disease development.

Mechanisms of IL-33 processing and secretion: differences and similarities between IL-1 family members

Interleukin-33 (IL-33) is the latest member of the IL-1 family that has become very attractive since the discovery of its major target cells, the innate lymphoid cells type 2 (ILC2), involved in the initiation of the type 2 immune response (secretion of IL-5 and IL-13) during parasitic infection and allergic diseases such as asthma. IL-33 is a chromatin-associated protein as it possesses in its N-terminus, a chromatin-binding domain, and is constitutively expressed in the nuclei of endothelial cells and in epithelial cells of tissues exposed to the environment. It is however, essential for IL-33 to be extracellularly released to bind to its receptor ST2 through the C-terminus portion of the protein in order to induce the inflammatory and type 2 responses. Like other IL-1 family members, IL-33 does not possess any signal peptide and may be released through unconventional secretory mechanisms or following cell damage and necrosis. It was initially believed that IL-33, like IL-1β and IL-18, requires processing by caspase-1 to be released, and for biological activity. On the contrary, full length IL-33 is biologically active, and processing by caspases results rather in IL-33 inactivation. Moreover, it has been recently shown that the bioactivity of IL-33 can be increased by inflammatory proteases secreted in the microenvironment, similarly to IL-1α, IL-1β and IL-18. This review will summarize recent progress on how IL-33 is released and processed compared with the other IL-1 family members, and how the immune cells recruited to the site of injury can regulate the disease-associated function of IL-33.

IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G

Interleukin-33 (IL-33) (NF-HEV) is a chromatin-associated nuclear cytokine from the IL-1 family, which has been linked to important diseases, including asthma, rheumatoid arthritis, ulcerative colitis, and cardiovascular diseases. IL-33 signals through the ST2 receptor and drives cytokine production in type 2 innate lymphoid cells (ILCs) (natural helper cells, nuocytes), T-helper (Th)2 lymphocytes, mast cells, basophils, eosinophils, invariant natural killer T (iNKT), and natural killer (NK) cells. We and others recently reported that, unlike IL-1β and IL-18, full-length IL-33 is biologically active independently of caspase-1 cleavage and that processing by caspases results in IL-33 inactivation. We suggested that IL-33, which is released upon cellular damage, may function as an endogenous danger signal or alarmin, similar to IL-1α or high-mobility group box 1 protein (HMGB1). Here, we investigated the possibility that IL-33 activity may be regulated by proteases released during inflammation. Using a combination of in vitro and in vivo approaches, we demonstrate that neutrophil serine proteases cathepsin G and elastase can cleave full-length human IL-33(1-270) and generate mature forms IL-33(95-270), IL-33(99-270), and IL-33(109-270). These forms are produced by activated human neutrophils ex vivo, are biologically active in vivo, and have a ~10-fold higher activity than full-length IL-33 in cellular assays. Murine IL-33 is also cleaved by neutrophil cathepsin G and elastase, and both full-length and cleaved endogenous IL-33 could be detected in the bronchoalveolar lavage fluid in an in vivo model of acute lung injury associated with neutrophil infiltration. We propose that the inflammatory microenvironment may exacerbate disease-associated functions of IL-33 through the generation of highly active mature forms.

Transgenic over-expression of interleukin-33 in osteoblasts results in decreased osteoclastogenesis

Interleukin-33 (IL-33) is the most recently identified member of the IL-1 family of cytokines, which is primarily known for its proinflammatory functions. We have previously reported that IL-33 is expressed by bone-forming osteoblasts, and that administration of recombinant IL-33 to bone marrow cultures inhibits their differentiation into bone-resorbing osteoclasts. Likewise, while the inhibitory effect of IL-33 on osteoclast differentiation was fully abolished in cultures lacking the IL-33 receptor ST2, mice lacking ST2 displayed low bone mass caused by increased osteoclastogenesis. Although these data suggested a physiological role of IL-33 as an inhibitor of bone resorption, direct in vivo evidence supporting such a function was still missing. Here we describe the generation and bone histomorphometric analysis of a transgenic mouse model (Col1a1-Il33) over-expressing IL-33 specifically in osteoblasts. While we did not observe differences in osteoblast number and bone formation between wildtype and Col1a1-Il33 mice, the number of osteoclasts was significantly reduced compared to wildtype littermates in two independent transgenic lines. Since we did not observe quantitative differences in the populations of eosinophils, neutrophils, basophils or M2-macrophages from the bone marrow of wildtype and Col1a1-Il33 mice, our data demonstrate that an inhibition of osteoclastogenesis is one of the major physiological functions of IL-33, at least in mice.

Production and functions of IL-33 in the central nervous system

Interleukin-33 (IL-33) is a novel multifunctional IL-1 family cytokine. IL-33 signals via a heterodimer composed of IL-1 receptor-related protein ST2 and IL-1 receptor accessory protein (IL-1RAcP). IL-33 has been shown to activate T helper 2 cells (Th2), mast cells and basophils to produce a variety of Th2 cytokines and mediate allergic-type immune responses. Recent studies have revealed that glial cells are induced to express IL-33 mRNA and protein. However, the functions of IL-33 and its producing cells in the central nervous system (CNS) are still uncertain. In this study, we investigated the expression and function of IL-33 in the CNS. IL-33 is produced by endothelial cells and astrocytes but not by microglia or neurons. The IL-33 receptors are expressed mainly in microglia and astrocytes. IL-33 dose-dependently induces the proliferation of microglia and enhances the production of pro-inflammatory cytokines, such as IL-1β and TNFα, as well as the anti-inflammatory cytokine IL-10. It also enhances chemokines and nitric oxide production and phagocytosis by microglia. Thus, IL-33 produced in the CNS activates microglia and may function as a pro-inflammatory mediator in the pathophysiology of the CNS.

Disease-associated functions of IL-33: the new kid in the IL-1 family

Interleukin-33 (IL-33), a newly described member of the IL-1 family, is expressed by many cell types following pro-inflammatory stimulation and is thought to be released on cell lysis. The IL-33 receptor, consisting of ST2 and IL-1 receptor accessory protein, is also widely expressed, particularly by T helper 2 (T(H)2) cells and mast cells. IL-33 is host-protective against helminth infection and reduces atherosclerosis by promoting T(H)2-type immune responses. However, IL-33 can also promote the pathogenesis of asthma by expanding T(H)2 cells and mediate joint inflammation, atopic dermatitis and anaphylaxis by mast cell activation. Thus IL-33 could be a new target for therapeutic intervention across a range of diseases.