Role Of IL-33 Research Articles

IL-22 mediates the oral mucosal wound healing via STAT3 in keratinocytes

ObjectiveWounds are common in the oral cavity. During wound healing, several cytokines are released, which are probably helpful in providing wound debridement, removal of damaged tissues and microbes. Most of the target cells of IL-22 are epithelial cells, which play an important role in mucosa immunity. DesignThe function of IL-22 in oral diseases is not well understood. We investigated the expression level of IL-22, collagen I and p-stat3 (Tyr705) via a mice tongue wound model in vivo and detected the effect of IL-22 on the expression of MMP-1, type I collagen and p-stat3 in keratinocytes. ResultsIL-22 and p-stat3 were associated with wound healing, and STAT3 was activated when the keratinocytes or the tongue tissue were stimulated by IL-22. In addition, IL-22 could mediate gene expression involved in wounds involving keratinocytes, such as type I collagen and MMP-1, which may contribute to scarless healing. ConclusionOur study suggests that IL-22 mediates wound healing via STAT3 in keratinocytes. This study reveals a new role for IL-22 in mediating wound healing.

Potential mechanism of IL-22 on microbial agents and cutaneous wound healing

Interleukin (IL)-22 structurally belongs to the IL-10 family of cytokines, which is expressed by Th22 cells, in addition to natural killer cells, lymphoid tissue inducer cells, lymphoid tissue inducer-like cells, and some other cells. Recently, the role of IL-22 in creating the protection and natural defense mechanism for controlling the bacterial infections, viral hemostasis, and the tissue recovery has been proved. IL-22 plays a protective role in wound healing of tissues such as skin. IL-22 acts by heterodimeric receptors consisting of IL-22R1 and IL-10R2. Human skin has the highest IL-22R1 expression among other tissues. The effect of IL-22 on skin tissue is related to the level of this cytokine and in a limited range has extraordinary wound healing effect, and out of this range, IL-22 may also have contradictory results. IL-22 provokes expression of molecules such as keratin 6, which provokes hyperplasia of reconstituted human epidermis. In addition, keratinocyte migration is increased by IL-22 stimulation.

IL-22 exacerbates weight loss in a murine model of chronic pulmonary Pseudomonas aeruginosa infection

BackgroundInterleukin (IL)-22 is a critical mediator of mucosal immunity and tissue regeneration, protecting against a number of respiratory pathogens. Whether IL-22 confers protection against chronic Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) is unknown. MethodsExplanted CF lungs were examined for IL-22 production and immune-localization. A murine model of persistent pulmonary PA infection was used to examine production of IL-22 following infective challenge. The role of IL-22 was examined using IL-22 knockout (KO) animals. ResultsIL-22 is produced within the adult CF lung and localizes to the airway epithelium. IL-22 is produced by murine pulmonary lymph node cells following lung infection. The absence of IL-22 resulted in no significant difference in acute mortality, bacterial burden, chronic infection rates, histological changes or neutrophilic inflammation in the chronic PA infection model. However, IL-22 KO animals lost less weight following infection. ConclusionIL-22 is produced in the CF lung and in response to PA infection yet is dispensable in protection against chronic pulmonary P. aeruginosa infection in a murine model. However, we identified a novel role for the cytokine in promoting infection-related weight-loss, a significant prognostic factor in the CF population.

Involvement of IL-37 in the Pathogenesis of Proliferative Diabetic Retinopathy.

Interleukin-37 is suggested as a novel proangiogenic factor in our previous study. In this study, the role of IL-37 was investigated in proliferative diabetic retinopathy (PDR). Vitreous fluids from 10 patients with PDR and 8 controls were collected. The levels of IL-37 were determined by ELISA and the relationship between IL-37 and VEGF-A/Ang-2 was analyzed. The effects of IL-37 on chorioretinal endothelial cell (RF/6A) proliferation, migration, and tube formation were determined by BrdU incorporation assay, Boyden chamber assay, scratch-wound assay and tube formation assay. The concentration of IL-37 in the PDR group was 95.09 ± 5.22 pg/mL and 34.91 ± 5.61 pg/mL in control group (P = 0.001). The level of IL-37 was highly related to the level of Ang-2 (P = 0.009, r = 0.772) and VEGF-A (P = 0.003, r = 0.827) in the PDR group, and VEGF expression in RF/6A cell was upregulated by IL-37 at low concentration. Interleukin-37 remarkably promoted RF/6A cell proliferation and migration. Interleukin-37 (1 ng/mL) remarkably stimulated tube formation with an increase of 85.3% for total tubule length and 74.1% for branching points compared with PBS control. The level of IL-37 is elevated in vitreous fluids of patients with PDR and correlates with the level of VEGF-A and Ang-2. Interleukin-37 stimulates proangiogenic response of retinal endothelial cells in vitro, suggesting the involvement of IL-37 in the pathogenesis of PDR.

IL-33 promotes food anaphylaxis in epicutaneously sensitized mice by targeting mast cells

Cutaneous exposure to food allergens predisposes to food allergy, which is commonly associated with atopic dermatitis (AD). Levels of the epithelial cytokine IL-33 are increased in skin lesions and serum of patients with AD. Mast cells (MCs) play a critical role in food-induced anaphylaxis and express the IL-33 receptor ST2. The role of IL-33 in patients with MC-dependent food anaphylaxis is unknown. We sought to determine the role and mechanism of action of IL-33 in patients with food-induced anaphylaxis in a model of IgE-dependent food anaphylaxis elicited by oral challenge of epicutaneously sensitized mice. Wild-type, ST2-deficient, and MC-deficient KitW-sh/W-sh mice were epicutaneously sensitized with ovalbumin (OVA) and then challenged orally with OVA. Body temperature was measured by means of telemetry, Il33 mRNA by means of quantitative PCR, and IL-33, OVA-specific IgE, and mouse mast cell protease 1 by means of ELISA. Bone marrow-derived mast cell (BMMC) degranulation was assessed by using flow cytometry. Il33 mRNA expression was upregulated in tape-stripped mouse skin and scratched human skin. Tape stripping caused local and systemic IL-33 release in mice. ST2 deficiency, as well as ST2 blockade before oral challenge, significantly reduced the severity of oral anaphylaxis without affecting the systemic TH2 response to the allergen. Oral anaphylaxis was abrogated in KitW-sh/W-sh mice and restored by means of reconstitution with wild-type but not ST2-deficient BMMCs. IL-33 significantly enhanced IgE-mediated degranulation of BMMCs invitro. IL-33 is released after mechanical skin injury, enhances IgE-mediated MC degranulation, and promotes oral anaphylaxis after epicutaneous sensitization by targeting MCs. IL-33 neutralization might be useful in treating food-induced anaphylaxis in patients with AD.

Intracellular NF-HEV/IL-33 harbors essential roles in Ras-induced cellular transformation by contributing to cyclin D1 protein synthesis

A member of the interleukin-1 family, interleukin-33 (NF-HEV/IL-33), is a ligand for the receptor, ST2L and stimulates the production of Th2 cytokines. Although IL-33 localizes to the nucleus and may be involved in the regulation of transcription independent of ST2L, its functions in the nucleus currently remain unclear. We herein demonstrated that the expression of IL-33 was markedly enhanced in NIH-3T3 cells transformed by an oncogenic H-Ras mutant (H-Ras (G12V)), and the induced IL-33 was mainly located in the nuclei of these cells. The enforced expression of IL-33 accelerated H-Ras (G12V)-induced transformation in NIH-3T3 cells, and this transforming activity was markedly reduced by the knockdown of IL-33 with shRNA. We subsequently analyzed several signaling molecules regulated by Ras in order to elucidate the mechanism by which IL-33 contributes to Ras (G12V)-induced transformation. We found that the knockdown of IL-33 effectively attenuated the Ras (G12V)-induced expression of cyclin D1. However, the knockdown of IL-33 failed to affect cyclin D1 mRNA expression levels, and epoxomicin, a proteasome inhibitor, did not cancel the IL-33 knockdown-induced down-regulation of its protein levels. We showed that Ras (G12V)-induced cyclin D1 protein synthesis was markedly suppressed by the knockdown of IL-33. Taken together, the results of the present study strongly suggest a novel role for IL-33 in cellular transformation.

PI3K/mTOR-dependent IL-22 production modulates polyfunctional T cell responses in viral hepatitis.

Abstract IL-22 is an important cytokine in modulating the consequences of inflammation in lesions, including the liver. However, the role of IL-22 in Lymphocytic Choriomeningitis Virus (LCMV)-induced viral hepatitis remains obscure. Here, we report that LCMV-induced IL-23 release promoted IL-22 production. And gdT cells and double negative T cells (DNT, CD3+ CD4− CD8− γδTCR− NK1.1−) were the main sources of IL-22 and IL-17 productions following LCMV infection in the liver. Interestingly, we also found that IL-23-stimulated IL-17 production in γδ T cells, and DNT cells were totally dependent on RORγt and PI3K/mTOR, but independent in AhR activities. Although IL-22 production in these two lymphocyte subsets depended on PI3K/mTOR, unlike IL-17 production, IL-22 production required additional signals from RORγt and AhR. Furthermore, IL-22 appeared to act as an important mediator in T cell responses in LCMV-induced viral hepatitis, despite the fact that the IL-22 receptor is restricted to being expressed on non-hematopoitic cells. IL-22−/− mice increased the recruitment of activated T cells to the liver and enhanced polyfunctional cytokine productions in effector CD4+ and CD8+ T cells in LCMV-induced acute or persistent viral hepatitis. Thus, our data revealed a novel connection between IL-23-PI3K/mTOR signaling pathway and the regulation of IL-22/IL-17 productions in the liver, and showed a novel role of IL-22 in modulating the plurifunctionality of anti-viral T cell responses during acute and persistent LCMV infection.

TGFβ inhibits IL-33-mediated mast cell activation in vitro and in vivo

Abstract TGFβ is involved in many pathological conditions, including autoimmune disorders, cancer, and cardiovascular and allergic diseases. We have previously found that TGFβ suppresses IgE-mediated mast cell activation in human and mouse mast cells in vitro. IL-33 is a recently discovered member of the IL-1 family that functions as an “alarmin” stimulating mast cell responses and enhancing IgE-mediated activation. How TGFβ affects IL-33 signaling is now known. We find that mouse bone marrow-derived mast cells cultured in TGFβ -1, -2, or -3 showed reduced IL-33-mediated production of TNF, IL-6, IL-13 and MCP-1, in a concentration-dependent manner. Furthermore, TGFβ also reduced expression of the IL-33 receptor ST2, as well as IL-33-mediated TAK1, IKB and ERK phosphorylation. TGF-β1 injection suppressed IL-33-mediated production of systemic inflammatory cytokines in vivo. The role of IL-33 in the pathogenesis of allergic diseases is incompletely understood. These findings, consistent with our previously reported effects of TGFβ on IgE-mediated activation, demonstrate that TGFβ can provide broad and substantial inhibitory signals to activated mast cells. These data suggest possible therapeutic strategies to maintain mast cell homeostasis in autoimmune and allergic diseases.

IL-33 is required for kidney ischemia-reperfusion-induced injury in mice

Abstract Introduction Ischemia-reperfusion (IR) injury during kidney transplantation induces necrosis of renal cells and the release of “alarmins” such as IL-33 that can activate the innate immune system, thereby triggering an inflammatory response and tissue damage leading to renal failure, dysfunction or rejection. The aim of this study was to investigate the contribution of IL-33 in kidney IR injury. Methods 10–12-week-old wild-type (WT) and IL-33-deficient (IL-33Gt/Gt) male C57/Bl6 mice were subjected to 32 minutes of unilateral kidney ischemia or a Sham operation. After 24 hours, kidneys were harvested and leucocyte infiltration (macrophages, neutrophils, NK and NKT cells) was analyzed by flow cytometry. Renal injury was assessed by measurement of plasma creatinine and histological grading. Results Plasma creatinine level and tissue damage significantly increased after renal IR in WT mice, as compared with Sham-operated animals, a difference that disappeared when WT mice were replaced by IL-33Gt/Gt mice. Even though intra-renal neutrophil (CD11b(+)GR-1(+)) were significantly increased 24 hour-post IR in both WT and IL-33Gt/Gt mice, this phenomenon was found to be significantly attenuated in IL-33Gt/Gt mice. Moreover, monocyte/macrophages (CD11b(+)F4/80(+)) and NKT cells, also known for their deleterious effect during renal IR injury, seemed to be less recruited 24 hour-post IR in IL-33Gt/Gt mice compared with WT mice. Conclusion IL-33Gt/Gt mice are less sensitive to kidney damage 24 hour-post IR, consistent with a deleterious effect of IL-33 during renal IR injury. This study underlines a new possible role of IL-33 as an innate-immune mediator during kidney IR injury.

The role of IL-33/ST2, IL-4, and eosinophils on the airway hyperresponsiveness induced by Strongyloides venezuelensis in BALB/c mice.

Strongyloidiasis is a neglected chronic nematode infection, in which the control of autoinfection rate and severity of disease is dependent on type 2 immune responses. Strongyloides also causes Th2 responses in the lung of infected animals and changes in airway function, including airway hyperresponsiveness (AHR). Mechanisms of AHR during Strongyloides venezuelensis infection are not entirely known, and we investigate here the role of IL-4, eosinophils, and IL-33/ST2. AHR was evaluated in infected mice by determining changes in lung function after increasing doses of methacholine. Balb/C, but no C57Bl/6, mice developed AHR, tissue eosinophilia, and increased local IL-4 and IL-5 production. Functional changes peaked at day 4 and 7, after the larva had left the lungs. AHR was clearly dependent on IL-4 but not on eosinophils, as evaluated by experiments in IL-4 and Gata-1-deficient mice. Experiments in ST2-deficient mice showed that this pathway was not needed for induction of AHR but was necessary for the maintenance of AHR and for Th2 responses in the lung. These studies clearly show a crucial role for IL-4 in the induction of AHR following S. venezuelensis infection and for IL-33/ST2 in maintaining AHR and lung Th2 responses.

The enigmatic role of IL-22 in asthma

ABSTRACTAsthma is a complex, heterogeneous disorder with increasing prevalence. It is now recognized that several asthma phenotypes exist, including type 2-high and type 2-low (or non-type 2) subsets. As current research strives to identify subgroups of asthmatics that share disease pathobiology to establish endotypes, efforts to clarify the underlying molecular mechanisms of disease are needed and essential. IL-22 is thought to be a mediator of asthma pathogenesis, but whether this cytokine has a pathologic or beneficial role in the lung during severe disease is still debated. Studies focused on the regulation of this cytokine by its receptors and other inflammatory mediators during allergic airway responses are necessary to clarify its role in disease. Here, we discuss the ambiguity surrounding the role of IL-22 in asthma and considerations for targeting IL-22 therapeutically.

Mechanism of glucocorticoid efficacy and resistance with chronic immune thrombocytopenia

Immune thrombocytopenia(ITP) is an autoimmune disorder, characterized by bone marrow cell dysmaturity and early destruction induced by autoantibodies against specific glycoproteins of platelet surface. As the fist-line therapy for ITP, glucocorticoid might control bleeding episodes in approximately 80%-90% of patients, leaving 20%-30% patients unresponsive to glucocorticoid therapy, and which troubles much. Studies indicate that glucocorticoid could inhibit the function of T effector cell by interfering the production, maturation, or function of dendritic cells(DC). High-dose dexamethasone interferes with the balance between interleukin (IL)-18 and IL-18 binding protein, which weakens the inducible role of IL-18 on interferon-γproduction, and turns to be immunosuppression. Glucocorticoid resistance may be associated with decreased glucocorticoid receptors(GR)α, increased GRβ, lower level expression of nuclear factor(NF)-κB and abnormal NF-κB mediated the downstream signal transduction. As coding gene of GR, NR3C1 gene takes much attention, but the role of NR3C1 or other encoding gene for GC resistance needs further research. Key words: Thrombocytopenia; Chronic disease; Glucocorticoids; Mechanism

P044. Roles of IL-33 on murine colitis and M2 macrophage differentiation in inflammatory bowel diseases

P044. Roles of IL-33 on murine colitis and M2 macrophage differentiation in inflammatory bowel diseases

IL-33 Promotes Food Anaphylaxis in Epicutaneously-Sensitized Mice By Targeting Mast Cells

Cutaneous exposure to food allergens predisposes to food allergy, which is commonly associated with atopic dermatitis (AD). The levels of the epithelial cytokine IL-33 are increased in skin lesions and serum of AD patients. Mast cells (MC) play a critical role in food anaphylaxis and express the IL-33 receptor ST2. The role of IL-33 in MC-dependent food anaphylaxis is unknown.We aim to determine the role and mechanism of action of IL-33 in food anaphylaxis in a model of IgE-dependent food anaphylaxis elicited by oral challenge of epicutaneously (EC)-sensitized mice. WT, ST2-deficient and MC-deficient KitW-sh/W-sh mice were EC sensitized with ovalbumin (OVA) then challenged orally with OVA. Body temperature was measured by telemetry, Il33 mRNA by qPCR, and IL-33, OVA-specific IgE and mouse mast cell protease 1 (mMCP-1) by ELISA. Bone marrow-derived MCs (BMMCs) degranulation was assessed by flow cytometry. Il33 mRNA expression was upregulated in tape-stripped mouse skin and scratched human skin, and tape stripping caused local and systemic IL-33 release in mice. ST2 deficiency, as well as ST2 blockade prior to oral challenge, significantly reduced the severity of oral anaphylaxis without affecting antigen-specific IgE or Th2 responses. Oral anaphylaxis was abrogated in KitW-sh/W-sh mice, and restored by reconstitution with WT, but not ST2-deficient, BMMCs. IL-33 significantly enhanced IgE-mediated degranulation of BMMCs in vitro. IL-33 is released following mechanical skin injury, enhances IgE-mediated MC degranulation, and promotes oral anaphylaxis following EC sensitization by targeting MCs. IL-33 neutralization may be useful in treating food anaphylaxis in AD patients.

Serum IL-33 Is Elevated in Children with Asthma and Is Associated with Disease Severity

Background: The role of IL-33, a member of the IL-1 family, in airway hyperresponsiveness and asthma has still to be fully understood. Objectives: This study is aimed at investigating serum IL-33 in children with asthma and its association with asthma severity. Methods: This age- and sex-matched case-control study comprised 61 children with asthma and 63 healthy controls. The mean age of the participants was 9.21 years (range: 6-14). Serum IL-33 was measured using ELISA and was compared between children with asthma and controls. In addition, the association of serum IL-33 with asthma severity was investigated. Results: The level of serum IL-33 was significantly higher in children with asthma than in controls (15.17 ± 32.3 vs. 0.61 ± 2.16 pg/ml; p = 0.028). It was significantly increased proportionately to asthma severity, namely 9.92 ± 30.26 pg/ml in children with mild asthma, 13.68 ± 29.27 pg/ml in children with moderate asthma and 31.92 ± 41.45 pg/ml in children with severe asthma (p = 0.026). Conclusion: Serum IL-33 is increased in children with asthma and is associated with disease severity.

Elevated levels of Interleukin (IL)-33 induce bone pathology but absence of IL-33 does not negatively impact normal bone homeostasis

Interleukin (IL)-33 is a member of the IL-1 family. IL-33 effects are mediated through its receptor, ST2 and IL-1RAcP, and its signaling induces the production of a number of pro-inflammatory mediators, including TNFα, IL-1β, IL-6, and IFN-γ. There are conflicting reports on the role of IL-33 in bone homeostasis, with some demonstrating a bone protective role for IL-33 whilst others show that IL-33 induces inflammatory arthritis with concurrent bone destruction. To better clarify the role IL-33 plays in bone biology in vivo, we studied IL-33 KO mice as well as mice in which the cytokine form of IL-33 was overexpressed. Mid-femur cortical bone mineral density (BMD) and bone strength were similar in the IL-33 KO mice compared to WT animals during the first 8months of life. However, in the absence of IL-33, we observed higher BMD in lumbar vertebrae and distal femur in female mice. In contrast, overexpression of IL-33 resulted in a marked and rapid reduction of bone volume, mineral density and strength. Moreover, this was associated with a robust increase in inflammatory cytokines (including IL-6 and IFN-γ), suggesting the bone pathology could be a direct effect of IL-33 or an indirect effect due to the induction of other mediators. Furthermore, the detrimental bone effects were accompanied by increases in osteoclast number and the bone resorption marker of C-terminal telopeptide collagen-I (CTX-I). Together, these results demonstrate that absence of IL-33 has no negative consequences in normal bone homeostasis while high levels of circulating IL-33 contributes to pathological bone loss.

Roles of IL-33 in Resistance and Tolerance to Systemic Candida albicans Infections.

IL-33 is a multifunctional cytokine that is released in response to a variety of intrinsic and extrinsic stimuli. The role of IL-33 in Candida albicans infections is just beginning to be revealed. This cytokine has beneficial effects on host defense against systemic C. albicans infections, and it promotes resistance mechanisms by which the immune system eliminates the invading fungal pathogens; and it also elevates host tolerance by reducing the inflammatory response and thereby, potentially, tissue damage. Thus, IL-33 is classified as a cytokine that has evolved functionally to protect the host from damage by pathogens and immunopathology.

Role of IL-33 and cathepsin G in cervical mucus of patients with recurrent miscarriage

Role of IL-33 and cathepsin G in cervical mucus of patients with recurrent miscarriage

Deletion of IL-18 Expression Ameliorates Spontaneous Kidney Failure in MRLlpr Mice.

The role of IL-18 in the pathogenesis of systemic lupus erythematosus is still not definitively solved. In this study, we generated MRLlpr mice, which develop a disease resembling systemic lupus erythematosus, genetically devoid of IL-18 expression. These mice in comparison to IL-18-competent MRLlpr mice show reduced signs of renal pathogenesis, while other parameters such as mean survival time, lymphadenopathy, constitutive interferon-γ production, and frequency of CD3+B220+ abnormal T cells were without differences. We conclude that in the systemic lupus erythematosus syndrom IL-18 is involved specifically in the renal pathogenesis.

IL-22 capacitates dermal fibroblast responses to TNF in scleroderma

ObjectivesInterleukin (IL) 22 mRNA in systemic sclerosis (SSc) skin and Th22 cells in SSc peripheral blood are increased, but the role of IL-22 in fibrosis development remains poorly understood.MethodsBiopsies were...