Role Of IL-33 Research Articles

The role of IL-33/ST2 system in the modulation of the immune response in infective endocarditis (a literature review)

An inflammatory process accompanied by a considerable number of pathological conditions in the body is one of the symptoms of infective endocarditis. The components of the immune system involved in the inflammatory response may serve as markers determining the development and prognosis of the disease and as potential therapeutic targets. These components include cytokines IL-33, sST2, and the IL-33/ST2 system, which are actively involved in the modulation of the inflammatory response. At present, the role of these biologically active molecules is well described for various pathologies associated with tissue destruction, including cardiovascular diseases, but not for the pathogenesis of infective endocarditis. This review is aimed at analyzing the available information on the pathogenesis of infective endocarditis, the role of IL-33 and ST2 in the formation of the inflammatory response in various pathological processes, and changes in the expression of the genes encoding these proteins under the influence of various factors.

Investigation of The Relationship Between IL-18 (-607 C/A), IL-18 (-137 G/C) Gene Variations and Ischemic Stroke Disease Development in Thrace Region of Turkey

ABSTRACT Background Ischemic stroke is a clinical condition characterized by focal or global cerebral dysfunction resulting from inhibition of brain blood flow. Genetic factors play an important role in the pathogenesis of ischemic stroke. As a result of IL-18 (−607 C/A, −137 G/C) gene variations, it is thought that binding of transcription factors may be affected and IL-18 mRNA expression can be modulated. Therefore, the purpose of our study is to investigate the roles of IL-18 (−607 C/A), IL-18 (−137 G/C) gene variations in the development of ischemic stroke in Trakya Region of Turkey. Methods Our study was performed with 90 ischemic stroke patients and 89 healthy controls. Genotype distributions of IL-18 (−607 C/A, −137 G/C) gene variations were determined using polymerase chain reaction (PCR) method. Results GC genotype and CA genotype of IL-18 (−137 G/C) and IL-18 (−607 C/A) gene variations were determined higher significantly in patent group as compared with other genotypes. However, the statistically significant difference was not determined between patients with ischemic stroke and healthy control groups in terms of IL-18 (−137 G/C) and IL-18 (−607 C/A) gene variations (p > 0,05). Allele frequencies of IL-18 (−137 G/C) and IL-18 (−607 C/A) in patient and control groups were significantly different from the Hardy-Weinberg distribution (p < .001 for all). Conclusion Although these gene variations’ genotype distributions were not determined as a genetic risk factor for the development of ischemic stroke, allele frequencies of IL-18 (−137 G/C) and IL-18 (−607 C/A) in patient and control groups were significantly different from the Hardy-Weinberg distribution.

IL-22 Plays a Critical Role in Maintaining Epithelial Integrity During Pulmonary Infection.

Pulmonary infection is a leading cause of hospitalization in world. Lung damage due to infection and host mediated pathology can have life threatening consequences. Factors that limit lung injury and/or promote epithelial barrier function and repair are highly desirable as immunomodulatory therapeutics. Over the last decade, interleukin−22 has been shown to have pulmonary epithelial protective functions at the mucosal immune interface with bacterial and viral pathogens. This article summarizes recent findings in this area and provides perspective regarding the role of IL-22 in mucosal host defense.

IL-22 Promotes IFN-γ-Mediated Immunity against Histoplasma capsulatum Infection.

Histoplasma capsulatum is the agent of histoplasmosis, one of the most frequent mycoses in the world. The infection initiates with fungal spore inhalation, transformation into yeasts in the lungs and establishment of a granulomatous disease, which is characterized by a Th1 response. The production of Th1 signature cytokines, such as IFN-γ, is crucial for yeast clearance from the lungs, and to prevent dissemination. Recently, it was demonstrated that IL-17, a Th17 signature cytokine, is also important for fungal control, particularly in the absence of Th1 response. IL-22 is another cytokine with multiple functions on host response and disease progression. However, little is known about the role of IL-22 during histoplasmosis. In this study, we demonstrated that absence of IL-22 affected the clearance of yeasts from the lungs and increased the spreading to the spleen. In addition, IL-22 deficient mice (Il22−/−) succumbed to infection, which correlated with reductions in the numbers of CD4+ IFN-γ+ T cells, reduced IFN-γ levels, and diminished nitric oxide synthase type 2 (NOS2) expression in the lungs. Importantly, treatment with rIFN-γ mitigated the susceptibility of Il22−/− mice to H. capsulatum infection. These data indicate that IL-22 is crucial for IFN-γ/NO production and resistance to experimental histoplasmosis.

Interleukin-22 receptor signaling in Paneth cells is critical for their maturation and antimicrobial function

Abstract Interleukin-22 (IL-22) acts in the intestine to promote critical tissue protective functions. However, since a diverse array of intestinal cell types (absorptive, secretory, and stem cells) express IL-22Ra1, a receptor for IL-22, it has been difficult to determine what cell type(s) specifically respond to IL-22 to mediate mucosal host defense. To address this question, we used entire gut epithelium, intestinal stem cell (ISC)-specific, and Paneth cell-specific IL-22Ra1 knockout mice. Entire epithelium-specific IL-22Ra1 knockout (Il22Ra1fl/fl;Villin-cre) mice displayed defects in Paneth cell function. Using ISC-specific IL-22Ra1 knockout mice (Il22Ra1fl/fl;Lgr5-EGFP-creERT2) and lineage tracing mice, we ruled out the involvement of Lgr5+ ISC-dependent IL-22Ra1 signaling in regulating the lineage commitment of epithelial cells, including Paneth cells. Using novel Paneth cell-specific IL-22Ra1 knockout mice (Il22Ra1fl/fl;Defa6-cre), we show that IL-22Ra1 signaling in Paneth cells is required for small intestinal host defense. We show that Paneth cell maturation, antimicrobial effector functions, gene expression of specific WNTs (Wnt6 and Wnt9b), and enteroid morphogenesis are dependent on cell-intrinsic IL-22Ra1 signaling. Furthermore, IL-22 signaling in Paneth cells regulates the intestinal commensal bacteria and microbiota-dependent IL-17A immune responses. Finally, we show Paneth cell-specific IL-22Ra1 signaling helps provide immunity against Salmonella typhimurium. Collectively, our findings provide a unique and novel role of IL-22 in Paneth cell-mediated small intestinal host defense.

IL-33, diet-induced obesity, and pulmonary responses to ozone

BackgroundObesity augments pulmonary responses to ozone. We have reported that IL-33 contributes to these effects of obesity in db/db mice. The purpose of this study was to determine whether IL-33 also contributes to obesity-related changes in the response to ozone in mice with diet-induced obesity.MethodsMale wildtype C57BL/6 mice and mice deficient in ST2, the IL-33 receptor, were placed on chow or high fat diets for 12 weeks from weaning. Because the microbiome has been implicated in obesity-related changes in the pulmonary response to ozone, mice were either housed with other mice of the same genotype (same housed) or with mice of the opposite genotype (cohoused). Cohousing transfers the gut microbiome from one mouse to its cagemates.ResultsDiet-induced increases in body mass were not affected by ST2 deficiency or cohousing. In same housed mice, ST2 deficiency reduced ozone-induced airway hyperresponsiveness and neutrophil recruitment in chow-fed but not HFD-fed mice even though ST2 deficiency reduced bronchoalveolar lavage IL-5 in both diet groups. In chow-fed mice, cohousing abolished ST2-related reductions in ozone-induced airway hyperresponsiveness and neutrophil recruitment, but in HFD-fed mice, no effect of cohousing on these responses to ozone was observed. In chow-fed mice, ST2 deficiency and cohousing caused changes in the gut microbiome. High fat diet-feeding caused marked changes in the gut microbiome and overrode both ST2-related and cohousing-related differences in the gut microbiome observed in chow-fed mice.ConclusionOur data indicate a role for IL-33 in pulmonary responses to ozone in chow-fed but not high fat diet-fed mice and are consistent with the hypothesis that these diet-related differences in the role of IL-33 are the result of changes in the gut microbiome.

Abstract A50: Interleukin-33 increases ST2+ regulatory T cells and promotes metastatic tumor growth in the lungs in an amphiregulin-dependent manner

Abstract Regulatory T cells (Tregs) can facilitate primary and metastatic tumor growth through the suppression of antitumor immunity. Emerging evidence suggests a distinct role for Tregs in tissue repair and tissue barrier integrity by IL-33 mediated activation of the IL-33 receptor (ST2), causing the production of the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG). Treg-derived AREG is critical for the repair of infection-induced damage in the lungs, and AREG may induce tumor cell proliferation, invasion, migration or resistance to apoptosis by signaling through EGFR. We have previously shown that immune-suppressive myeloid-derived suppressor cells (MDSCs), macrophages, and Tregs are recruited to the lungs of mice bearing metastatic mammary tumors and promote metastatic growth in the lungs. We now show that IL-33 is dramatically increased in and around metastatic tumor foci in the lungs of mice bearing metastatic murine mammary tumors. We have also found that the majority of Tregs in the lungs of metastatic tumor-bearing mice express ST2, that Tregs express significantly more ST2 than conventional T cells, and that ST2+ Tregs produce significantly more AREG than ST2- Tregs. The intranasal administration of recombinant IL-33 increased the proportion of AREG producing ST2+ Tregs and enhanced the level of phosphorylated EGFR (pEGFR) in the metastatic lungs. While recombinant AREG did not impact the proliferation of mammary tumor cells in vitro despite inducing a dose-dependent increase in pEGFR, intranasal administration of recombinant AREG resulted in a ten-fold increase in pulmonary metastatic tumor burden in vivo. Further, the intranasal administration of recombinant IL-33 significantly increased metastatic tumor burden in the lungs in an AREG-dependent manner. These data identify ST2+ Tregs as a microenvironmental source of AREG in the lungs of metastatic mammary tumor-bearing mice and show that inhibition of AREG can reduce IL33-mediated increases in metastatic tumor growth. Our findings highlight an important role for IL33 and AREG in promoting metastatic growth and support the development of therapeutic strategies to inhibit AREG to reduce tumor metastases in the lungs. Citation Format: Elizabeth C. Halvorsen, S. Elizabeth Franks, Brennan J. Wadsworth, Bryant T. Harbourne, Rachel A. Cederberg, Catherine A. Steer, Itziar Martinez-Gonzalez, Jack Calder, William W. Lockwood, Kevin L. Bennewith. Interleukin-33 increases ST2+ regulatory T cells and promotes metastatic tumor growth in the lungs in an amphiregulin-dependent manner [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A50.

Decreased IL-37 expression in hepatocellular carcinoma tissues and liver cancer cell lines.

The role of IL-37 in cancer is currently largely unknown. The present study aimed to investigate IL-37 expression in hepatocellular carcinoma (HCC), paracancerous tissues (PT) and liver cancer cell lines, and their associations between IL-37 and NF-κB. A total of 65 HCC and 65 PT tissues were collected. The expression of IL-37 and NF-κB in tissues was detected by immunohistochemistry (IHC) and the data was analyzed using SPSS software. In the in vitro studies, IL-37 gene was transfected into HepG2 and MHCC97H cell lines with Lipofectamine 3000, and the protein regulation of NF-κB by IL-37 was verified by immunofluorescence (IF) and western blotting. In HCC, the positive expression rates of IL-37 and NF-kB were 21.5 and 95.4%, respectively. In PT, strong positive staining of IL-37and weak positive staining of NF-κB were observed. The normal expression levels of IL-37 and NF-κB, the increased IL-37 and decreased NF-κB induced by IL-37 gene transfection were observed through IF in cell lines. In terms of clinical significance, the difference in IL-37 expression between HCC and PT was statistically significant (χ2=55.05; P<0.001). IL-37 expression in HCC but not PT was negatively associated with serum AFP (χ2=6.522; P=0.039). IL-37 expression in PT was associated with sex (χ2=13.12; P=0.003) and tumor size (χ2=7.996; P=0.045). NF-κB expression in PT was associated with age, sex and BCLC stage. Notably, there was a negative correlation between IL-37 and NF-κB in HCC (r=−0.277; P=0.029) but not in PT (P>0.05). IL-37 overexpression downregulated the NF-κB protein by 56.50% in HepG2 cells (P<0.05) and 30.52% in MHCC97H cells (P<0.05). In conclusion, the expression of IL-37 in HCC and PT was specifically associated with serum AFP and tumor size, respectively. IL-37 expression was negatively correlated with NF-κB protein expression in HCC tissues and liver cancer cell lines.

Abstract WMP76: Interleukin-33 Protects Against Transient Ischemic Stroke by Enhancing Regulatory T-Cell Expansion and Accumulation

Background: The interleukin (IL)-33 could promote proliferation of regulatory T lymphocytes (Tregs) which are negatively related with brain damage after ischemic stroke. How IL-33 works on Tregs after stroke is unclear. The purpose of this study was to investigate the role of IL-33 for Tregs-mediated neuroprotection and further expounded the mechanisms of protection in mice. Methods: In vitro study, primary mice neuronal cells were subjected to 3h oxygen-glucose deprivation (OGD). The vehicle or drug conditioned Tregs were applied to neurons at the time of induction of hypoxia respectively. Neuronal apoptosis, Tregs related cytokines were measured by MTT assay, Western blotting and enzyme-linked immune-sorbent assay (ELISA). In vivo study, Tregs were depleted by intraperitoneal administration of anti-CD25Ab. Intraperitoneal injection of IL-33 immediately post 60 min transient middle cerebral artery occlusion (tMCAO) modeling. The neurological function test at days 1, 3, 5, 7 and 14 after tMCAO. Infarct volume, Brain edema, cell death, percentage of Tregs and related cytokines were respectively measured by 2,3,5-triphenyltetrazolium chloride or MAP2 staining, dry-wet method, TUNEL staining, flow cytometry and immunofluorescence, Western blotting and ELISA. Results: The supernatant of IL-33-treated Tregs reduced neuronal apoptosis in the OGD model meanwhile elevated the production of Tregs related cytokines IL-10, IL-35 and TGF- β in vitro. Intraperitoneal administration of IL-33 significantly reduced infarct volume and stroke-induced cell death and improved sensorimotor functions. Notably, the protective effect of IL-33 was abolished in mice depleted of Tregs. IL-33 increased CD4+CD25+Foxp3+ Tregs in spleens, blood, and brain in vivo. Yet, ST2 blocking muted these IL-33 activities. Mechanistically, the protection of IL-33 was associated with reduced apoptosis protein and production of Tregs related cytokine. Conclusions: This study elucidated that IL-33 afforded neuroprotection against ischemic brain injury by enhancing ST2-dependent regulatory T-cell expansion and activation, which suggested a promising immune modulatory target for the treatment of stroke.

Enhanced Type 2 Immune Reactions by Increased IL-22/IL-22Ra1 Signaling in Chronic Rhinosinusitis With Nasal Polyps.

PurposeRecent studies have revealed the pathogenic role of interleukin (IL)-22 in atopic dermatitis and asthma. However, little is known about the role of IL-22 in the pathophysiology of chronic rhinosinusitis with nasal polyps. We aimed to investigate the expression of IL-22 and its pathogenic function in type 2 immune reactions of nasal polyps (NP).MethodsProtein levels of inflammatory mediators were determined by multiplex immunoassay, and principal component analysis (PCA) was performed. Immunofluorescence analysis and mast cell culture were used to determine the cellular sources of IL-22. Normal human bronchial epithelial (NHBE) cells were stimulated using IL-22 in combination with diverse cytokines, and thymic stromal lymphopoietin (TSLP) was measured.ResultsIL-22 expression was not up-regulated in NP compared with control tissues, but IL-22-high NP revealed distinct features characterized by type 2 inflammatory cytokines such as chemokine (C-C motif) ligand (CCL)-11, CCL-24, and IL-5 on the PCA. Additionally, IL-22 positively correlated with type 2 immune mediators and the disease severity in NP. For the localization of the cellular sources of IL-22 in eosinophilic NP, it was expressed in cells mostly composed of eosinophil peroxidase-positive cells and partially of tryptase-positive cells. The human mast cell line, LAD2 cells, released IL-22 mediated by immunoglobulin E. Moreover, IL-22 receptor subunit alpha-1 (IL-22Ra1) expression was significantly increased in NP. IL-22Ra1 was up-regulated with poly(I:C) stimulation in NHBE cells. Furthermore, TSLP production was enhanced when stimulated with a combination of IL-13, poly(I:C), and IL-22. Treatment with anti-IL-22Ra1 also inhibited IL-22-induced enhancement of TSLP production.ConclusionIL-22 was associated with type 2 inflammatory reactions in NP. The IL-22/IL-22Ra1 axis was enhanced and might be involved in type 2 inflammatory reactions via TSLP production in NP.

IL-37/ STAT3/ HIF-1α negative feedback signaling drives gemcitabine resistance in pancreatic cancer.

Human interleukin (IL)-37 is a member of the IL-1 family with potent anti-inflammatory and immunosuppressive properties. Previously, it has been reported that IL-37 suppresses tumor growth and progression. However, the roles of IL-37 in pancreatic cancer development and chemo-resistance remain unknown.Methods: Immunohistochemistry was used to analyze the correlation between IL-37 expression and clinicopathological features of pancreatic ductal adenocarcinoma (PDAC). Western-blot and RT-PCR was used to verify the correlation between IL-37 and hypoxia-inducible factor (HIF)-1α. We performed chromatin immunoprecipitation and luciferase assays to validate HIF-1α suppression of IL-37 expression. Moreover, gain- and loss-of-function studies in vitro and in vivo were used to demonstrate the biological function of IL-37 on PDAC development and chemo-resistance.Results: Our results showed that IL-37 expression was remarkably decreased in PDAC tissues when compared to adjacent normal pancreatic tissues. Reduced IL-37 expression in PDACs was associated with increased PDAC histological grade, tumor size, lymph node metastasis and vessel invasion. IL-37 low patients also have remarkably shorter relapse-free and overall survival. Importantly, IL-37 expression was positively correlated with Gemcitabine efficacy. Mechanistically, HIF-1α attenuated IL-37 transcription by binding to the hypoxia response elements (HREs) in IL-37 promoter. Conversely, IL-37 suppressed HIF-1α expression through STAT3 inhibition. Functionally, downregulation of IL-37 in PDAC cells promoted chemo-resistance, migration and progression in vivo and in vitro.Conclusions: Collectively, our data uncovered IL-37/ STAT3/ HIF-1α negative feedback signaling drives Gemcitabine resistance in PDAC.

Interleukin-22 in Allergic Airway Diseases: A Systematic Review

The immune system plays an important role in the pathogenesis of many disorders, including allergic airway diseases. There are studies suggesting that interleukin (IL)-22 can be important in the development of these diseases. However, it is not known if this cytokine acts as proinflammatory or anti-inflammatory agent. This systematic review aimed to analyze level and role of IL-22 in patients with allergic airway diseases in comparison with healthy individuals. Systematic review included only observational studies with patients having allergic rhinitis and/or allergic asthma. The primary outcome measure was IL-22 level in patients with allergic asthma and/or allergic rhinitis. A total of 95 articles were found. Overall, 6 articles were included in systematic review. Five of these studies showed that IL-22 was increased in patients with allergic airway diseases compared with control group. Majority of studies revealed relation between IL-22 level and severity of allergic asthma and allergic rhinitis. Some studies showed positive relation between IL-22 level and total immunoglobulin E (IgE), specific IgE, and eosinophil count in nasal mucosa. IL-22 level is increased in children and adults with allergic airway diseases and is likely to be associated with proinflammatory features.

TRIM30 modulates Interleukin-22-regulated papillary thyroid Cancer cell migration and invasion by targeting Sox17 for K48-linked Polyubiquitination

BackgroundInterleukin-22 (IL-22) belongs to the IL-10 cytokine family and is mainly produced by activated Th1 cells. Although IL-22 expression is reported to be elevated in many cancers, and increased IL-22 expression correlates with tumor progression and poor prognosis, little is known about the role of IL-22 in papillary thyroid cancer (PTC). We previously demonstrated that IL-22 promotes PTC cell migration and invasion through the microRNA-595/Sox17 axis.MethodsWe used qRT-PCR and western blot to determine TRIM30, Sox17 and β-catenin expression in PTC cells. Knockdown and overexpression were performed to detect the role of TRIM30/Sox17/β-catenin axis on the migration and invasion PTC cells. Co-IP were used to determine the interaction between TRIM30 and Sox17.FindingsIn this study, we demonstrated that IL-22 triggered tripartite-motif protein 30 (TRIM30) association with Sox17, thereby mediating K48-linked polyubiquitination of Sox17. We then demonstrated that TRIM30 was a positive regulator of IL-22-regulated migration and invasion of PTC cells. We also found that IL-22 induced the transcriptional activity of β-catenin and translocation of β-catenin from cytosol to the nucleus. Upon investigating the mechanisms behind this event, we found that IL-22 disrupted Sox17/β-catenin interactions by inducing TRIM30/Sox17 interactions, leading to promotion of β-catenin-dependent signaling. The analysis of hundreds of clinical specimens revealed that IL-22, TRIM30 and β-catenin levels were upregulated in PTC tissues compared with normal thyroid, and that their expression levels were closely correlated. Taken together, under the influence of IL-22, by sequestration of Sox17, TRIM30 promotes β-catenin-dependent signaling that promotes PTC cell proliferation.

The role of IL-33 in preventing metabolic disease

The role of IL-33 in preventing metabolic disease

Possible Roles of IL-33 in the Innate-Adaptive Immune Crosstalk of Psoriasis Pathogenesis.

Background IL-33 belongs to the IL-1 family, playing a role in several biologic processes as well as in the pathogenesis of different diseases, including skin pathologies. It acts as an alarmin, released by damaged cells. Binding to a ST2 receptor, it stimulates many immune cells such as ILC2 and Th2 cells. IL-33/ST2 axis seems to be involved in Th17 response. According to this, a review was performed to analyze if IL-33 even interplay in the onset of psoriasis, a Th1/Th17 inflammatory disease. Methods Data obtained from the included articles are study author name, publication date, group studied, clinical and biological variables, laboratory tests, and outcome of interest of the study. Results Data are obtained from the 19 studies identified, which assessed the association between IL-33 and psoriasis. Discussion It seems to promote the innate-adaptive immune crosstalk: it could induce mast cells and neutrophil response after being released by injured keratinocytes and after stimulation by some cytokines, in particular TNFα, INFγ, and IL-17A. In addition, it seems to be involved from the onset of disease to the development of comorbidities, as psoriatic arthritis. Conclusion The core of the future research on psoriasis could be to fully understand the role of this complex cytokine, in order also to find a new therapeutic approach.

Dysregulated Interleukin -33/ST2 Pathway Perpetuates Chronic Inflammation in Hashimoto's Thyroiditis.

Hashimoto's Thyroiditis (HT) is an autoimmune disease, characterized by chronic inflammation of the thyroid gland with unknown etiologies. Recently, interleukin-33/ST2 (IL- 33/ST2) pathway reveals its participation in the process of several autoimmune diseases. In this study, the role of IL-33/ST2 pathway in the development of HT is investigated. The levels of plasma IL-33, sST2 and the frequency of circulating CD4+ST2L+T cells in 30 HT patients and 20 healthy controls were determined by enzyme-linked immunosorbent assay (ELISA) and flow cytometry respectively. The mRNA expressions of related molecules in IL-33/ST2 pathway in thyroid tissues (12 HT patients and 10 controls) were detected by real-time quantitative PCR (RTqPCR). The protein expressions of IL-33 and ST2 were determined by Western blot and immunohistochemistry staining. The mRNA expressions of plasma IL-33 and sST2 were elevated in HT patients, with an increased ratio of IL-33/sST2. The number of CD4+ST2L+ T cells in PBMCs of HT group was significantly increased when compared to the control group (CON) by Flow cytometry assay. MRNA Expression of IL-33 and ST2 in thyroid tissue and the level of IL-1β and IL-18 were significantly upregulated in HT patients, while IL-5 was down-regulated in HT patients, compared to CON. The expression of IL-1β and IL-18 were positively correlated with the expression of IL-33. Results of western blot and immunohistochemical staining were consistent with qPCR. IL-33/ST2 pathway participates in HT via affecting the production of inflammatory cytokines.

Research progress on the role of IL-33/ST2 axis in pathogenesis of allergic rhinitis

SummaryThe binding of IL-33 and its receptor ST2 plays a key role in the development of cardiovascular diseases, chronic inflammation, allergic diseases and fibrosis related diseases. The study of the relationship between IL-33/ST2 signaling pathway and these diseases may provide new ideas and methods for the diagnosis and treatment of diseases. Although many high-quality studies have been done on the role of IL-33/ST2 signaling pathway in the pathogenesis of allergic rhinitis, there is still a lack of comprehensive and clear explanation. This paper reviews the role of IL-33/ST2 signaling pathway in the pathogenesis of allergic rhinitis on the basis of literature review. This signaling pathway can be used to guide the treatment of allergic rhinitis in theory.

P5374Genetic deletion of IL-22 increased cardiac rupture after myocardial infarction in mice

Abstract Background Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, which mainly targets epithelial cells and does not target immune cells. Recently, it has been reported that IL-22 play roles in tissue repair in the skin and the liver; however, role of IL-22 in the process of tissue repair after myocardial infarction (MI) is unknown. Here, we investigated the role of IL-22 in tissue repair process after MI. Methods and results First, we examined the expression of IL-22 and its receptor IL-22RA1 in the wild type (WT) mice by real-time PCR. The expression of IL-22 and IL-22RA1 in the hearts were significantly increased 3 days after MI (p&lt;0.05). To clarify the role of IL-22 in the heart after MI, we produced MI model in the WT mice and IL-22 knockout (KO) mice. We found that the IL-22 KO mice had significantly higher mortality than the WT mice after MI (p&lt;0.05). Approximately 80% of the IL-22 KO mice died with cardiac rupture after MI. The infarct size which was estimated by evans blue dye and triphenyltetrazolium chloride staining at 3 days after MI was comparable between the IL-22 KO mice and the WT mice. Next, we performed real time PCR and PCR array analysis for tissue fibrosis and repair genes. We found that alpha-smooth muscle actin (aSMA), NF-kB, TNF-a and MMP13 (also known as collagenase-3) were significantly increased in the infarct area of IL-22 KO mice compared to WT mice. Immunostaining showed that the myofibroblast marker aSMA positive cells in the border area after MI were markedly higher in the IL-22 KO mice compared with the WT mice (p&lt;0.05). Approximately 70% of cardiac rupture after MI in the IL-22 KO mice were occurred in the infarct area adjacent to the border area. Furthermore, we found aSMA positive cells and MMP13 positive cells around the ruptured site of the heart. Conclusion Thus, IL-22 KO mice exhibit high mortality and increased cardiac rupture after MI. And expression of aSMA and MMP13 were highly expressed in the ruptured site after MI in the IL-22 KO mice. These results suggest that IL-22 may play an important role in the tissue repair process after MI.

Extracellular IL-37 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the PI3K/AKT signaling pathway

Interleukin (IL)-37, a pivotal anti-inflammatory cytokine and a fundamental inhibitor of innate immunity, has recently been shown to be abnormally expressed in several autoimmune-related orthopedic diseases, including rheumatoid arthritis, ankylosing spondylitis, and osteoporosis. However, the role of IL-37 during osteogenic differentiation of mesenchymal stem cells (MSCs) remains largely unknown. In this study, extracellular IL-37 significantly increased osteoblast-specific gene expression, the number of mineral deposits, and alkaline phosphatase activity of MSCs. Moreover, a signaling pathway was activated in the presence of IL-37. The enhanced osteogenic differentiation of MSCs due to supplementation of IL-37 was partially rescued by the presence of a PI3K/AKT signaling inhibitor. Using a rat calvarial bone defect model, IL-37 significantly improved bone healing. Collectively, these findings indicate that extracellular IL-37 enhanced osteogenesis of MSCs, at least in part by activation of the PI3K/AKT signaling pathway.

P6287Analysis of novel cardiac markers sST2 and IL-33 in chronic heart failure with reduced ejection fraction

Abstract Background Soluble (s) ST-2 has been recently evaluated as a monitoring parameter in heart failure (HF). Besides being a marker for cardiac strain and hemodynamic stress, studies also found an influence of ST2 on the immune system, above all mediated through its Janus-Face ligand IL-33, an alarmin released under stress conditions or by cellular death. In contrast to sST2, the role of IL-33 in HF is yet unknown. Objective In this project, we aimed for an analysis of the ST2/IL33 pathway in patients with heart failure with reduced ejection fraction (HFrEF). Methods In total, 200 patients were included in the study: 59 with ischemic (ICM), 65 with dilated (DCM) cardiomyopathy (mean LVEF 38%), as well as 76 control patients without coronary artery disease or signs of heart failure. Serum samples were analyzed by use of ELISA after informed consent. Results sST2 showed a significant elevation in all HF patients (p&lt;0.0001) compared to the control group. No significant differences in levels of sST2 were observed between ICM and DCM patients. In contrast to sST2, no differences between HF patients and control group were observed for IL-33. Furthermore, sST2 showed a significant correlation with CRP (p&lt;0.001, r=0.28), NT-pro-BNP (p&lt;0.0001, r=0.40) and an inverse correlation with ejection fraction (p&lt;0.0001, r=−0.40). Additionally, sST2 showed a significant elevation in patients in NYHA stages I-II (p=0.030) and NYHA stages III-IV (p&lt;0.01). Again, no significant correlations were observed between IL-33 and parameters mentioned above. Analysis of sST2 in heart failure Conclusions We observed a significant increase and correlation with disease severity of sST2 in chronic HFrEF patients of both ischemic and non-ischemic origin, but contrary to our expectations, no significant changes in serum levels of IL-33. Thus, a mechanism independent of ST2/IL33 axis could be responsible of sST2 secretion in HF. Further studies including acute decompensated patients could provide a better understanding of the IL-33 role in HF.