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1
Dwyer, Gaelen K., Lisa R. Mathews, Anna Lucas, Bruce R. Blazar, and Heth R. Turnquist. "Recipient conditioning contributes to IL-33-driven Th1 alloimmune responses following rapid ST2 upregulation on donor CD4+ T cells during lymphopenia-induced proliferation." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 55.4. http://dx.doi.org/10.4049/jimmunol.200.supp.55.4.
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Abstract IL-33 is augmented in recipient tissues by conditioning before allogeneic stem cell transplantation (alloSCT) and is a required signal to donor T cell for GVHD. Targetable mechanisms by which IL-33 supports GVHD are yet undefined. Conditioning causes lymphopenia-induced proliferation (LIP) and releases microbial products. These products promote myeloid cell secretion of IL-12, which induces the IL-33 receptor, ST2, on T cells in vitro. We hypothesized that IL-12 induces ST2 on donor T cells during LIP promoting IL-33 augmentation of the Th1 responses leading to GVHD. To establish the role of IL-12 in T cell ST2 expression and IL-33-mediated GVHD, irradiated BALB/c mice were given B6 alloSCT and T cells. Some mice received IL-12p40 neutralizing Ab or control Ab alone, with or without concurrent IL-33 administration. To test the impact of lymphopenia on T cells, ST2−Foxp3−CD4+ T cells alone or with ST2+ Treg were transferred into B6 Rag2−/−γc−/− mice. Mice received PBS or IL-33 on days 1–8. Neutralizing IL-12 did not reduce ST2 on T cells after alloSCT nor rescue mice from IL-33-mediated acceleration of GVHD. Post-alloSCT, IL-33 worked with IL-12 to expand ST2+Tbet+ Th1 cells. Neutralizing IL-12, but not delivery of IL-33, increased Gata3+ Th2 cells after alloSCT. During LIP, CD4+Foxp3− T cells rapidly upregulated ST2 independent of IL-33, but IL-33 then favored the expansion of Th1 cells, even in the presence of ST2+ Treg. These data suggest that CD4+ T cells rapidly upregulate ST2 during alloSCT conditioning induced lymphopenia. After alloSCT, IL-33 does not support Treg or Th2 cells, but works with IL-12 to augment Th1 responses and GVHD. Blocking stimuli that induces ST2 on proliferating donor CD4+ T cells may be effective for limiting GVHD.
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Matta, Benjamin, Jeremy Lott, Lisa Mathews, Brian Rosborough, and Heth Turnquist. "CD11c+ dendritic cells are required for IL-33-mediated expansion of ST2+Foxp3+ regulatory T cells in vivo (P1075)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 121.9. http://dx.doi.org/10.4049/jimmunol.190.supp.121.9.
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Abstract IL-33 is an IL-1 cytokine that signals via ST2, which is expressed on T cells and myeloid cells. Although IL-33 promotes Th2 responses, its administration potently expands CD4+Foxp3+ regulatory T cells (Treg). We examined if IL-33 expands murine Treg directly or indirectly through its impact on CD11c+ DC. The ability of IL-33 to facilitate CD3/CD28-stimulated proliferation of wild-type (WT) or ST2-/- Treg was compared to IL-2. The impact of IL-33 on the capacity of DC to expand Treg was defined in vitro on bone marrow (BM)-generated DC from WT or ST2-/- mice and in vivo using CD11c-DTR BM chimeras administered diphtheria toxin (DT) to deplete CD11c+ cells during IL-33 treatment. The capacity of IL-33-expanded Treg from Foxp3-RFP reporter mice to suppress effector T cells was assessed. We found that IL-33 directly expands Treg in vitro, including an ST2+ subset absent from IL-2-treated cultures. IL-33-exposed DC generate ST2+ Treg from naïve T cells, and is dependent on ST2 expressed by DC. IL-33 failed to expand Treg in vivo, especially ST2+ Treg, in the absence of CD11c+ cells. In conclusion, IL-33 promotes the expansion of suppressive Foxp3+ Treg, including an ST2+ subset in vitro and in vivo. This results from IL-33 activity directly on Treg, but more significantly, indirectly through its impact on CD11c+ cells. These findings have important implications for further characterization of ST2+ Treg and the development of novel therapeutics aimed at promoting immune tolerance.
3
Zhao, Qing, and Guangjie Chen. "Role of IL-33 and Its Receptor in T Cell-Mediated Autoimmune Diseases." BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/587376.
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Interleukin-33 (IL-33) is a new cytokine of interleukin-1 family, whose specific receptor is ST2. IL-33 exerts its functions via its target cells and plays different roles in diseases. ST2 deletion and exclusion of IL-33/ST2 axis are accompanied by enhanced susceptibility to dominantly T cell-mediated organ-specific autoimmune diseases. It has been reported that IL-33/ST2 pathway plays a key role in host defense and immune regulation in inflammatory and infectious diseases. This review focuses on new findings in the roles of IL-33 and ST2 in several kinds of T cell-mediated autoimmune diseases.
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Matta, Benjamin, Jeremy Lott, Lisa Mathews, Brian Rosborough, Bruce Blazar, and Heth Turnquist. "IL-33 stimulates dendritic cell secretion of IL-2 that promotes selective expansion of ST2+Foxp3+ regulatory T cells (IRC5P.460)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 125.9. http://dx.doi.org/10.4049/jimmunol.192.supp.125.9.
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Abstract IL-33 is a pleiotropic IL-1 family cytokine that signals via ST2 and expands ST2+Foxp3+ regulatory T cells (Treg) in vivo. As ST2+ Treg show poor expansion by direct IL-33 stimulation, we sought to define mechanisms mediating their expansion. IL-2 signaling promotes ST2 expression on CD4+ T cells, and dendritic cells (DC) express ST2 (able to respond to IL-33), and are a potential source of IL-2. Thus, we examined if IL-33 mediates ST2+ Treg expansion by stimulating DC IL-2 production. CD11c+ wild type (WT) or IL-2 knockout (KO) bone marrow DC were exposed to IL-33 or LPS. DC phenotype was evaluated by multi-color flow cytometric analysis. The influence of IL-33 DC on T cell function was evaluated in MLR with CD4+ T cells, and T cell proliferation and phenotype were determined by flow analysis. Cytokines were quantitated by ELISA. We found that unlike LPS, IL-33 does not influence DC surface phenotype or induce pro-inflammatory cytokine production compared to controls. However, IL-33 induces a 5-fold increase IL-2 production by DC. In MLR, IL-33 DC selectively expand an activated subset of ST2+Foxp3+ Treg that are CD44hiICOShi. IL-33 DC-derived IL-2 is critical since IL-33-exposed IL-2 KO DC fail to expand ST2+ Treg. In summary, IL-33 licenses DC to selectively expand a subset of activated Treg through production of IL-2, in the absence of classical DC activation. These findings may be harnessed to aid the development of novel therapeutics aimed at promoting immune tolerance.
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Song, Yitian, Fangzhi Wei, Ying Liu, Feng Han, Lihui Ma, Yanping Zhuang, Chengdan Pan, Zhandong Jia, and Aimin Gong. "IL-33/ST2 Activation Is involved in Ro60-Regulated Photosensitivity in Cutaneous Lupus Erythematosus." Mediators of Inflammation 2022 (July 20, 2022): 1–15. http://dx.doi.org/10.1155/2022/4955761.
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Interleukin- (IL-) 33 contributes to various inflammatory processes. IL-33/ST2 activation participates in systemic lupus erythematous via binding to the receptor of Suppression of Tumorigenicity 2 protein (ST2). However, whether IL-33/ST2 interferes with the nosogenesis of cutaneous lupus erythematosus (CLE) has not been reported so far. Herein, we proposed to disclose the impacts on IL-33/ST2 activation and Ro60 on CLE and their potential implications in the photosensitization of CLE cells. IL-33, ST2, and Ro60 in CLE patients’ skin lesions were detected. Murine keratinocytes stimulated with or without IL-33 were irradiated by ultraviolet B (UVB), and the levels of Ro60 and inflammation markers were determined. Keratinocytes were cocultured with J774.2 macrophages and stimulated with IL-33 for analysis of chemostasis. The results identified that IL-33, ST2, and downstream inflammation markers were significantly upregulated in CLE lesions with Ro60 overexpression. Additionally, IL-33 treatment promoted the upregulation of Ro60 induced by UVB treatment in murine keratinocytes. Moreover, IL-33 stimulates keratinocytes to induce macrophage migration via enhancing the generation of the chemokine (C–C motif) ligands 17 and 22. Meanwhile, the silencing of ST2 or nuclear factor-kappa B (NF-κB) suppression abolished IL-33-induced upregulation of Ro60 in keratinocytes. Similarly, the inhibition of SOX17 expression was followed by downregulation of Ro60 in keratinocytes following IL-33 stimulation. In addition, UVB irradiation upregulated SOX17 in keratinocytes. Conclusively, the IL-33/ST2 axis interferes with Ro60-regulated photosensitization via activating the NF-κB- and PI3K/Akt- and SOX17-related pathways.
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Zhang, Xiaoli, Benjamin M. Matta, Dawn K. Reichenbach, Bruce R. Blazar, and Heth R. Turnquist. "Suppression of Tumorigenicity 2 (ST2) signaling is required for regulatory T cell control of Graft-vs. Host Disease." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 140.20. http://dx.doi.org/10.4049/jimmunol.196.supp.140.20.
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Abstract How IL-33-mediated signals impact on ST2-expressing regulatory T cell (Treg) expansion and regulatory functions is poorly understood. To establish the importance of direct IL-33 stimulation of Treg for control of alloimmune responses, we utilized a rodent model of graft-vs. host disease (GVHD) where C57BL/6 mice were irradiated and given a BALB/c bone marrow transplant (BMT) along with BALB/c CD4+ CD25+ Treg from st2+/+ or st2−/− mice at a 1:2 ratio with WT BALB/c CD3+ effector T cells. As expected, WT st2+/+ CD4+ CD25+ cells promoted full protection against GVHD with 90% of recipients receiving st2+/+ CD4+ CD25+ free of GVHD at Day 100 post-BMT. However, only 10% of mice that received st2−/− Treg achieved long-term survival (p=0.0017, st2+/+ v. st2−/−). Associated mechanistic studies revealed that Treg frequency was significantly reduced in recipients receiving st2−/− Treg compared to those receiving st2+/+ Treg. To define the signaling patterns IL-33 generates in Treg, fluorescence activated cell sorting was used to obtain ST2− or ST2+ Treg cells from the splenocytes of Foxp3 reporter mice and IL33 activated signaling downstream of ST2 was quantitated by phosphoflow cytometry. This analysis revealed that IL-33 signaling via ST2 on Treg activates both NF-κB and p38 MAPK. Yet, only IL-33-stimulated p38 MAPK, but not NF-kB, signaling was required for ST2+ Treg expansion. Our studies make two important observations regarding how IL-33 stimulation of Treg supports immune regulation. First, we demonstrate that IL-33 activates p38 MAPK to drive selective ST2+ Treg expansion. Second, we show that IL-33-mediated signals are critical to the capacity of Treg to control the alloimmune responses leading to GVHD.
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Han, Jae Ho, Chang-Hee Suh, Ju-Yang Jung, Mi-Hyun Ahn, Ji Eun Kwon, Hyunee Yim, and Hyoun-Ah Kim. "Serum Levels of Interleukin 33 and Soluble ST2 Are Associated with the Extent of Disease Activity and Cutaneous Manifestations in Patients with Active Adult-onset Still’s Disease." Journal of Rheumatology 44, no. 6 (April 1, 2017): 740–47. http://dx.doi.org/10.3899/jrheum.170020.
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Objective.Interleukin 33 (IL-33), a member of the IL-1 family and a ligand of the orphan receptor ST2, plays key roles in innate and adaptive immunity. We examined the associations between IL-33/ST2 levels and clinical manifestations of patients with active adult-onset Still’s disease (AOSD).Methods.Blood samples were collected from 40 patients with active AOSD, 28 patients with rheumatoid arthritis (RA), and 27 healthy controls (HC). The serum levels of IL-33 and soluble ST2 were determined using ELISA. Expression levels of IL-33 and ST2 in biopsy specimens obtained from 34 AOSD patients with rash were immunohistochemically investigated.Results.IL-33 levels of patients with AOSD were higher than those of patients with RA and HC. Soluble ST2 levels of patients with AOSD were higher than those of HC, but not of patients with RA. Serum IL-33 levels correlated with systemic score, erythrocyte sedimentation rate, ferritin levels, and aspartate transaminase levels. However, serum soluble ST2 levels correlated only with ferritin levels. The numbers of inflammatory cells expressing IL-33 and ST2 were elevated in skin lesions of patients with AOSD compared to HC, but did not differ from those of the skin lesions of eczema or psoriasis.Conclusion.We found significantly higher serum IL-33 and soluble ST2 levels in patients with active AOSD. Results indicate that the IL-33/ST2 signaling pathway may play a role in the pathogenesis of the acute inflammation and skin manifestations associated with AOSD.
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Dong, Yonghua, Hua Hu, Dandan Fu, Shuting Zheng, Qingqing Wang, Keshav K C, Xiangfeng Song, and Zhongwei Tian. "Serum Expression of IL-33 and ST2 in Patients with Psoriasis Vulgaris." Archives of Iranian Medicine 24, no. 9 (September 1, 2021): 689–95. http://dx.doi.org/10.34172/aim.2021.99.
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Background: Psoriasis vulgaris (PsV) is an immune-mediated skin disease of unknown mechanism. Interleukin 33 (IL-33) is a member of IL-1 cytokine family and suppression of tumorigenicity 2 (ST2) is the specific ligand of IL-33. It has been found that IL-33 and ST2 are increased in psoriatic lesions, but the expression levels in serum and their relationship to clinical features are still unclear. The aim of this study is to assess IL-33, ST2, IL-17 and IL-5 serum levels as well as serum concentration of blood glucose and blood lipids in PsV patients and their relationship with clinical characteristics. Methods: Sixty-eight PsV samples and 60 healthy individuals were recruited. Serum levels of IL-33, ST2, IL-17 and IL-5 were measured by enzyme-linked immunosorbent assay and blood glucose and blood lipid were assayed by automatic biochemical analyzer. Results: Serum levels of IL-33, ST2, IL-17 and IL-5 were increased significantly in PsV patients compared with controls (P<0.01). Cytokines were overexpressed in PsV patients during active stages compared with controls (P<0.05). Expression levels of IL-33, ST2 and IL-17 confirmed a significance in different severity groups of PsV patients (P<0.05). Serum concentration of triglyceride (TG) was also increased compared with controls (P=0.024). IL-33 levels were positively correlated with total cholesterol (TC) levels (r=0.319, P=0.008). Conclusion: IL-33/ST2 could generally reflect the activity and disease severity in PsV patients, which indicates that the IL-33/ST2 signaling pathway plays an important role in the pathogenesis of PsV.
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Johnston, Laura K., Chia-Lin Hsu, Rebecca A. Krier-Burris, Krishan D. Chhiba, Karen B. Chien, Andrew McKenzie, Sergejs Berdnikovs, and Paul J. Bryce. "Eosinophil lineage commitment and IL-5-dependent expansion is regulated by IL-33 in mice." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 191.7. http://dx.doi.org/10.4049/jimmunol.196.supp.191.7.
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Abstract Eosinophils are important in the pathogenesis of many diseases, including asthma, eosinophilic esophagitis and eczema. While IL-5 is necessary for the maturation of eosinophil progenitors (EoP) into mature eosinophils (EoM), the signals that promote commitment to the eosinophil lineage are unknown. The IL-33 receptor, ST2, is expressed on several inflammatory cells, including eosinophils, and is best characterized for its role during the initiation of allergic responses in the peripheral tissues. Recently, ST2 expression was described on hematopoietic stem cells, where its function remains unclear. Here, we sought to determine whether IL-33 and ST2 contribute to hematopoietic lineage decisions. We found that both IL-33- and ST2-deficient mice exhibited diminished peripheral blood eosinophils at baseline. Correspondingly, IL-33 administration increased EoM as well as IL-5 in the blood and bone marrow in WT and IL-33-deficient but not ST2-deficient mice. Blocking IL-5 with a neutralizing antibody prevented IL-33-expanded EoP from maturing into EoM, while transgenic overexpression of IL-5 in ST2-deficient mice resulted in significantly lower hypereosinophilia than transgenic IL-5 mice. Finally, we observed that IL-33, but not IL-5, specifically expanded EoP and upregulated IL-5Rα on EoP as well as increased IL-5 after bone marrow was cultured for three days. Our findings identify a basal defect in eosinophilopoiesis in IL-33- and ST2-deficient mice. Furthermore, we establish unappreciated roles for IL-33 and ST2 in eosinophil development via progenitor regulation and define a mechanism whereby IL-33 licenses commitment into the eosinophil lineage by driving both responsiveness to IL-5 and IL-5 production.
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Li, Yun-Qiu, Yu Zhong, Xu-Ping Xiao, Dan-Dan Li, Zheng Zhou, and Yan-Yan Tian. "IL-33/ST2 axis promotes the inflammatory response of nasal mucosal epithelial cells through inducing the ERK1/2 pathway." Innate Immunity 26, no. 6 (May 26, 2020): 505–13. http://dx.doi.org/10.1177/1753425920918911.
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Allergic rhinitis (AR) is a nasal mucosal inflammatory disease mediated by environmental allergens. At present, the relationship between the IL-33/ST2 axis, ERK1/2 pathway and AR progression needs further exploration. In our study, an AR model was constructed in vitro by treating HNEpC cells with Der p1. qRT-PCR was applied to assess the mRNA levels of IL-33, ST2, TNF-α, IL-6, and IL-8. Western blotting was used to measure the protein levels of IL-33, ST2, and the downstream proteins p-ERK1/2, ERK1/2, p-RSK, and RSK. IL-6, IL-8, IL-33, and TNF-α protein levels in cell supernatants were evaluated by ELISA. Flow cytometry was performed to check cell apoptosis of HNEpC in the presence or absence of Der p1. Our results indicate that the relative levels of IL-33, ST2, TNF-α, IL-6, and IL-8 were increased significantly in the AR model group. The above effects were notably reversed after transfection with shIL-33 or shST2. IL-33 stimulation further resulted in the increase in both ST2 and inflammation-associated cytokines, and these effects were restored after shST2 treatment. Also, the levels of inflammatory factors induced by IL-33 stimulation or ST2 overexpression were reversed after applying an ERK1/2 pathway blocker. In conclusion, IL-33/ST2 mediated inflammation of nasal mucosal epithelial cells by inducing the ERK1/2 pathway.
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Begum, Salma, Barry E. Perlman, Nuriban Valero-Pacheco, Valerie O’Besso, Tracy Wu, Sara S. Morelli, Aimee M. Beaulieu, and Nataki C. Douglas. "Dynamic Expression of Interleukin-33 and ST2 in the Mouse Reproductive Tract Is Influenced by Superovulation." Journal of Histochemistry & Cytochemistry 68, no. 4 (February 28, 2020): 253–67. http://dx.doi.org/10.1369/0022155420911049.
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Interleukin-33 (IL-33) is an IL-1 family cytokine with pleiotropic effects on diverse cell types. Dysregulated IL-33 signaling has been implicated in pregnancy-related disorders, including preeclampsia and recurrent pregnancy loss, and in ovarian function in women undergoing controlled ovarian stimulation for in vitro fertilization. To date, expression of IL-33 and its receptor subunit, ST2, in the female reproductive tract remains poorly characterized. We identify IL-33-expressing oocytes surrounded by ST2-expressing granulosa cells at all stages of follicular development, in addition to IL-33+ and ST2+ non-endothelial cells in the ovarian stroma and theca layer in ovaries from adult mice. These expression patterns are similar in estrus- and diestrus-stage adults and in pubescent mice, suggesting a role for IL-33 signaling in ovarian function throughout development and in the estrous cycle. In the uterus, we find expression of IL-33 and ST2 in glandular and luminal epithelia during estrus and at the initiation of pregnancy. Uterine IL-33 expression was modulated by the estrous cycle and was reduced in pubescent females. Last, superovulation increases transcripts for IL-33 and the soluble form of ST2 (sST2) in ovaries, and for IL-33 in uteri. Collectively, our findings lay the foundation for studies identifying cell type-specific requirements for IL-33/ST2 signaling in the establishment and maintenance of mouse pregnancy.
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Chen, Wei-Yu, Tzu-Hsien Tsai, Jenq-Lin Yang, and Lung-Chih Li. "Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases." Cellular Physiology and Biochemistry 49, no. 1 (2018): 349–58. http://dx.doi.org/10.1159/000492885.
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Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses via interaction with its receptor, ST2. Activation of ST2 signalling by IL-33 triggers pleiotropic immune functions in multiple ST2-expressing immune cells, including macrophages, neutrophils, eosinophils, basophils, mast cells, type 2 helper T cells, regulatory T cells, and group 2 innate lymphoid cells. IL-33-mediated effector functions contribute to the tissue inflammatory and reparative responses in various organs including lung, skin, kidney, central nerve system, cardiovascular system, and gastrointestinal system. Endogenous IL-33/ ST2 signaling exhibits diverse immune regulatory functions during progression of different diseases. IL-33 likely functions as a disease sensitizer and plays pathological roles in inflamed tissues in allergic disorders that involve hyperreactive immune responses in the context of skin and pulmonary allergy. However, IL-33 also mediates tissue-protective functions during the recovery phase following tissue injury in the central nerve system and gastrointestinal system. Modulation of the IL-33/ST2 axis, therefore, represents a promising strategy for treating immune disorders that involve dysregulation of the cytokine signalling. In the past two decades, therapeutic strategies blocking IL-33/ST2 have been extensively studied for the treatment of diseases in animal models. In this review, the current progress on the development of therapeutic biologics for targeting IL-33/ST2 signalling in inflammatory diseases is summarized.
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Liu, Quan, Jeremy M. Lott, Lisa R. Mathews, Huihua Li, Qiang Zhu, Benjamin M. Matta, Greg M. Delgoffe, Ming-Hui Fan, and Heth R. Turnquist. "IL-33-Driven Innate Tissue-Protective Function of ST2+ Treg Cells." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 51.7. http://dx.doi.org/10.4049/jimmunol.196.supp.51.7.
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Abstract Non-lymphoid tissue-resident CD4+ Foxp3+ regulatory T (Treg) cells with the capacity to modulate non-immunological processes including organismal metabolism and tissue repair have been recently described. Notably, a large fraction of non-lymphoid tissue-resident Treg cells express ST2, the receptor for the tissue-derived cytokine and alarmin, IL-33. However, the relationship between IL-33 and ST2+ Treg cells in quiescent and pathogenic states is only starting to be understood. Using FACS and Foxp3 reporter mice, we demonstrate that ST2+ Treg cells from naïve animals are phenotypically and functionally unique relative to ST2− Treg isolated from the same location. Yet, our studies establish that peripheral and lymphoid tissue ST2+ Treg cells are highly comparable. Interestingly, ST2+ Treg exhibit a high level of aerobic glycolysis, which supports their augmented potential for cytokine secretion, especially that of IL-5, IL-10, and IL-13. IL-5 and IL-13 secretion in response to IL-33 is an innate function of ST2+ Treg cells as it does not require TCR-stimulation. Conversely, ST2+ Treg release of other cytokines, including IL-10, is antigen-restricted and amplified by IL-33. Among Treg subsets, ST2+ Treg cells are the exclusive source of Type 2 cytokines, especially IL-13, which we reveal supports Treg reparative responses. Using mice deficient in IL-33 or Treg cells, we establish that Treg cells and IL-33 are both required to protect mice from lethal lung injury. In line with these data, delivery of IL-13, but not IL-33, at the time of lung injury rescues Treg-depleted mice. This study establishes that ST2+ Treg cells possess an innate capacity for cytokine production that is crucial to tissue repair and inflammation control.
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Wang, Xuan, Xiaoqing Shao, Xinhao Liu, Qiu Qin, Jian Xu, and Jin A. Zhang. "Dysregulated Interleukin -33/ST2 Pathway Perpetuates Chronic Inflammation in Hashimoto’s Thyroiditis." Endocrine, Metabolic & Immune Disorders - Drug Targets 19, no. 7 (October 11, 2019): 1012–21. http://dx.doi.org/10.2174/1871530319666190226164309.
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Objective: 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. Methods: 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. Results: 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. Conclusion: IL-33/ST2 pathway participates in HT via affecting the production of inflammatory cytokines.
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Roessing, Anna, Aravind Cherukuri, David Rothstein, and Heth Roderick Turnquist. "Foxp3+ regulatory T cell expression of IL-10 is required for IL-33-mediated expansion of regulatory B cells." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 80.13. http://dx.doi.org/10.4049/jimmunol.198.supp.80.13.
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Abstract BACKGROUND FoxP3+ regulatory T cells (Tregs) are crucial to self- and antigen-specific tolerance. IL-33 drives expansion of Tregs expressing the IL-33 receptor, ST2, and secreting high levels of IL-10. Regulatory B cells (Bregs) are recently identified negative regulators of the immune system and depend on IL-10 to suppress effector T cell responses. In new data, we find that IL-33 also expands Bregs, however, the relationship between ST2+ Treg and Bregs cells remains unknown. Herein we elucidated if a directional relationship exists between IL-33-expanded Bregs and Tregs. METHODS B6 eGFP-FoxP3-Diptheria Toxin (DT) receptor mice were used to establish whether IL-33-expanded Treg were needed for IL-33-aided increases of TIM-1+ IL-10+ Bregs. B6 Foxp3-Cre X IL-10fl/fl mice were used to determine the need for IL-10 expression by Tregs for IL-33-mediated expansion of Bregs. RESULTS Assessment of splenocytes for Tregs and Bregs by flow cytometry showed that IL-33 administration led to a 3–5-fold increase in ST2+ Tregs. IL-33 also led to a 3-fold increase in the frequency of IL-10+ Breg, most of which expressed ST2. A lack of Tregs hindered the ability of IL-33 to increase Bregs. While Treg expression IL-10 was not required for ST2+ Treg expansion by IL-33, IL-10 expression by Tregs is crucial for Breg expansion by IL-33. CONCLUSIONS We have uncovered a relationship between Tregs and Bregs in response to IL-33. Specifically, while we show that Bregs express ST2, our data suggest that IL-33 expansion of Bregs is indirectly mediated by Treg IL-10 production.
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Ohno, Tatsukuni, Susumu Nakae, and Miyuki Azuma. "Paracrine IL-33 stimulation enhances lipopolysaccharide-mediated macrophage activation (117.30)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 117.30. http://dx.doi.org/10.4049/jimmunol.186.supp.117.30.
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Abstract BACKGROUND: IL-33, a member of the IL-1 family of cytokines, provokes Th2-type inflammation accompanied by accumulation of eosinophils through IL-33R, which consists of ST2 and IL-1RAcP. We previously demonstrated that macrophages produce IL-33 in response to LPS. Some immune responses were shown to differ between ST2-deficient mice and soluble ST2-Fc fusion protein-treated mice. Even in anti-ST2 antibody (Ab)-treated mice, the phenotypes differed between distinct Ab clones, because the characterization of such Abs (i.e., depletion, agonistic or blocking Abs) was unclear in some cases. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the precise role of IL-33, we newly generated neutralizing monoclonal Abs for IL-33. Exogenous IL-33 potentiated LPS-mediated cytokine production by macrophages. That LPS-mediated cytokine production by macrophages was suppressed by inhibition of endogenous IL-33 by the anti-IL-33 neutralizing mAbs. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that LPS-mediated macrophage activation is accelerated by macrophage-derived paracrine IL-33 stimulation.
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Reichenbach, Dawn K., Vincent Schwarze, Benjamin M. Matta, Victor Tkachev, Elizabeth Lieberknecht, Quan Liu, Brent H. Koehn, et al. "Regulation of Immune Responses during Acute GvHD Via the IL-33/ST2 Axis." Blood 124, no. 21 (December 6, 2014): 844. http://dx.doi.org/10.1182/blood.v124.21.844.844.
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Abstract The IL-1 superfamily member IL-33 is produced in barrier tissues. IL-33 binds to the receptor suppression of tumorigenicity 2 (ST2), expressed on stromal cells, regulatory T cells (Tregs), myeloid derived suppressor cells (MDSCs), and macrophages. IL-33 has both anti-inflammatory and pro-inflammatory properties. It is not known if IL-33 plays a role in acute GvHD, and if so what properties it exerts. By immunohistochemistry staining of gut tissues, IL-33 production by non-hematopoietic cells was increased in mice post-conditioning and in patients during GvHD. To determine whether IL-33 could augment GvHD via a host signaling mechanism, we compared st2-/-to wildtype (wt) hosts and observed decreased GvHD lethality (Figure 1A). Additionally, IL-33-/- versus wt hosts had a marked decrease in GvHD lethality and reduced TNFα production. Conversely, IL-33 administration during the peak inflammatory response worsened GvHD. Previous studies have shown increased levels of the soluble form of ST2 (sST2) are a biomarker for steroid-refractory GvHD (Vander Lugt, NEJM, 2013). We hypothesized that sST2 acted not only as an indicator of tissue injury and biomarker of GvHD but also as an immune modulator during GvHD. In rodents, we found that ST2 was upregulated on alloreactive T cells and sST2 increased as GvHD progressed. St2-/-versus wt donor T cells had a marked reduction in GvHD lethality (Figure 1B) without compromise of graft-vs-leukemia responses. Comparable data was seen in 2 different strain combinations. Alloantigen-induced IL-18 receptor upregulation was significantly lower in the absence of ST2, which was linked to significantly reduced IFNγ production by st2-/- vs wt CD4 and CD8 T cells during GvHD. Similarly, sST2 transgenic hosts and wt recipients given exogenous sST2-Fc fusion protein infusions (Figure 1C) to block ST2/IL-33 interaction each had significantly reduced GVHD lethality, establishing the functional role of ST2 as a decoy receptor modulating GVHD. During the peak of the GvHD inflammatory response, IL-33 signalling of either donor or host cells promoted activation of donor T cells, while the use of exogenous sST2-Fc protein to prevent IL33/ST2 engagement ameliorates disease. Together, these studies point to targeting of the IL-33/ST2 axis as a novel and potent target for GvHD therapy. Disclosures Warncke: Novartis Pharma AG: Employment. Junt:Novartis Pharma AG: Employment.
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Tonacci, Alessandro, Paolina Quattrocchi, and Sebastiano Gangemi. "IL33/ST2 Axis in Diabetic Kidney Disease: A Literature Review." Medicina 55, no. 2 (February 14, 2019): 50. http://dx.doi.org/10.3390/medicina55020050.
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Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, playing a role in inflammatory, infectious and autoimmune diseases and expressed in the cellular nucleus in several tissues. High levels of IL-33 are expressed in epithelial barrier tissues and endothelial barriers. ST2 is a receptor for IL-33, expressed selectively on a subset of Th2 cells, mediating some of their functions. The IL-33/ST2 axis plays an important role in several acute and chronic inflammatory diseases, including asthma and rheumatoid arthritis. Different disorders are related to the activity of IL-33, ST2, or their axis, including cardiovascular disease or renal disturbances. Therefore, in the present work, a literature review was conducted, covering the period from 1 January 2000 to 30 November 2018, in PubMed, ScienceDirect, and Google Scholar database, to assess the involvement of the IL-33/ST2 axis in diabetic kidney disease. 6 articles directly dealing with the argument were identified, highlighting a clear link between IL-33/ST2 axis and diabetic kidney disease or related nephropathy. Overall, the involvement of ST2 seems to be more predictive than IL-33, especially in investigating the deterioration of kidney function; however, both compounds are pivotal in the field of renal diseases. Future studies are required to confirm the scientific evidences on larger and more heterogeneous cohorts.
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Mathias, Clinton B., Dylan Krajewski, Marcela T. Taruselli, Jeffrey Rovatti, Mohamed Mire, Sallie S. Schneider, and John J. Ryan. "Interleukin-10 enhances IL-33-mediated MC activation and modulates the development of food allergy." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 49.11. http://dx.doi.org/10.4049/jimmunol.208.supp.49.11.
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Abstract We recently demonstrated an unexpected, proinflammatory role for the pleiotropic cytokine, IL-10, in promoting mast cell (MC) responses during food allergy. IL-10 enhanced MC proliferation and survival and promoted IgE-dependent responses to enteric ovalbumin (OVA) challenge. However, whether the effects of IL-10 on MCs extend beyond IgE-mediated signaling is not clear. To determine whether IL-10 can prime MC activation mediated by IgE-independent stimuli, we assessed the effects of rIL-10 on IL-33-stimulated bone marrow-derived MCs (BMMCs) and examined the development of food allergy in IL-10-depleted ST2−/− mice. IL-10 co-culture significantly enhanced the activity and cytokine production of both IgE and IL-33-activated MCs. Furthermore, the production of MC-derived cytokines such as IL-13 was suppressed in IL-33-stimulated IL-10−/− BMMCs, which could be restored by addition of exogenous IL-10. IL-10 enhanced MC FcɛRI and ST2 expression. Further, ST2−/− BMMCs demonstrated that IL-10 enhanced IgE-mediated activation in the absence of autocrine IL-33 signaling. To assess the role of IL-10 in vivo, food allergy was measured in WT and ST2−/− mice subjected to antibody-mediated IL-10 depletion. IL-10-depleted WT mice exhibited a significant attenuation in allergic diarrhea and MC-mediated responses to OVA challenge. Similarly, ST2−/− mice also exhibited a profound suppression of MC-mediated responses, demonstrating the importance of IL-33 in MC regulation. IL-10 depletion had no additional effects in ST2−/− mice. However, IL-10/ST2−/− mice exhibited a further decrease in OVA-IgE and MC activation compared to ST2−/− mice. Our data reveal a novel role for IL-10 in enhancing both IgE and IL-33-mediated MC responses. This project was supported by funds from the National Institutes of Health grants: NIAID R15AI107668 (CBM)
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Rostan, Octavie, Muhammad Imran Arshad, Claire Piquet-Pellorce, Florence Robert-Gangneux, Jean-Pierre Gangneux, and Michel Samson. "Crucial and Diverse Role of the Interleukin-33/ST2 Axis in Infectious Diseases." Infection and Immunity 83, no. 5 (February 23, 2015): 1738–48. http://dx.doi.org/10.1128/iai.02908-14.
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Interleukin-33 (IL-33) has now emerged as a cytokine with diverse and pleiotropic functions in various infectious and inflammatory diseases. IL-33 is expressed by epithelial cells, endothelial cells, fibroblasts, and hepatocytes. The target cells of IL-33 are Th2 cells, basophils, dendritic cells, mast cells, macrophages, NKT cells, and nuocytes, newly discovered natural helper cells/innate lymphoid cells bearing the ST2 receptor. IL-33 has dual functions, both as a traditional cytokine and as a nuclear factor that regulates gene transcription. IL-33 functions as an “alarmin” released following cell death, as a biomarker, and as a vaccine adjuvant, with proinflammatory and protective effects during various infections. The exacerbated or protective role of the IL-33/ST2 axis during different infections is dependent upon the organ involved, type of infectious agent, whether the infection is acute or chronic, the invasiveness of the infectious agent, the host immune compartment, and cellular and cytokine microenvironments. In this review, we focus on recent advances in the understanding of the role of the IL-33/ST2 axis in various viral, bacterial, fungal, helminth, and protozoal infectious diseases gained from animal models and studies in human patients. The functional role of IL-33 and ST2 during experimentally induced infections has been summarized by accumulating the data for IL-33- and ST2-deficient mice or for mice exogenously administered IL-33. In summary, exploring the crucial and diverse roles of the IL-33/ST2 axis during infections may help in the development of therapeutic interventions for a wide range of infectious diseases.
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Atamas, Sergei, Edward Pickering, Pavel Kopach, Phillip Kang, Virginia Lockatell, John Papadimitriou, Andrew McKenzie, and Irina Luzina. "Full-length IL-33 acts differently from mature IL-33 in vivo partially in an ST2-independent fashion (120.30)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 120.30. http://dx.doi.org/10.4049/jimmunol.188.supp.120.30.
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Abstract IL-33 is a key regulator of inflammation and immunity. It remains controversial whether protease-mediated activation of IL-33 is needed for functional effects. We constructed and validated recombinant adenoviruses for gene delivery of full-length mouse (flm) and mature mouse (mm) (aa 109-266) IL-33 to mouse lungs in vivo. Gene expression was confirmed by RT-Q-PCR and ELISA. Analyses of BAL samples and lung tissues revealed substantial differences between flmIL-33 and mmIL-33. Both isoforms caused pulmonary infiltration and BAL influx of T and B lymphocytes and neutrophils, whereas mmIL-33 also caused significant pulmonary eosinophilia (~47-55% of BAL cell count) and hyperplasia of mucus-producing goblet cells. Multiplex analyses showed that mmIL-33 caused significant increases in IL-4, IL-5, IL-13, IL-17, and KC; flmIL-33 tended to stimulate IFN-γ; and both isoforms induced MCP-1 with a greater increase induced by mmIL-33. Subsequent analyses were performed in mice deficient of ST2 (IL-33 receptor). ST2 deficiency completely abrogated mmIL-33-induced pulmonary eosinophilia, goblet cell hyperplasia, and elevations in IL-4 and IL-5. However, lymphocytic infiltration induced by flmIL-33 or mmIL-33 was attenuated but persistent in the absence of ST2. These data suggest that full-length IL-33 is independently functionally active in vivo, in part in an ST2-independent fashion, and that Th2 effects but not lymphocytosis induced by mature IL-33 are ST2-dependent.
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Aggeletopoulou, Ioanna, Efthymios P. Tsounis, and Christos Triantos. "Molecular Mechanisms Underlying IL-33-Mediated Inflammation in Inflammatory Bowel Disease." International Journal of Molecular Sciences 24, no. 1 (December 30, 2022): 623. http://dx.doi.org/10.3390/ijms24010623.
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Interleukin-33 (IL-33) is a cytokine defined by its pleiotropic function, acting either as a typical extracellular cytokine or as a nuclear transcription factor. IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), interact with both innate and adaptive immunity and are considered critical regulators of inflammatory disorders. The IL-33/ST2 axis is involved in the maintenance of intestinal homeostasis; on the basis of their role as pro- or anti-inflammatory mediators of first-line innate immunity, their expression is of great importance in regard to mucosal defenses. Mucosal immunity commonly presents an imbalance in inflammatory bowel disease (IBD). This review summarizes the main cellular and molecular aspects of IL-33 and ST2, mainly focusing on the current evidence of the pro- and anti-inflammatory effects of the IL-33/ST2 axis in the course of ulcerative colitis and Crohn’s disease, as well as the molecular mechanisms underlying the association of IL-33/ST2 signaling in IBD pathogenesis. Although IL-33 modulates and impacts the development, course, and recurrence of the inflammatory response, the exact role of this molecule is elusive, and it seems to be associated with the subtype of the disease or the disease stage. Unraveling of IL-33/ST2-mediated mechanisms involved in IBD pathology shows great potential for clinical application as therapeutic targets in IBD treatment.
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St. Rose, Marie-Clare, Naomi Tsurutani, Adam Adler, and Anthony Vella. "Defining the role of the alarmin IL-33 during the CD8 T cell effector response (VAC3P.958)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 73.20. http://dx.doi.org/10.4049/jimmunol.192.supp.73.20.
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Abstract ST2, the receptor for the alarmin IL-33, is expressed on CD8 T cells and both IL-33 and ST2 can optimize anti-viral CD8 T cell immune responses. Further, signaling through ST2 in combination with innate-derived cytokines such as IL-12 can induce TCR-independent production of IFN-gamma. We sought to understand the role of the IL-33/ST2 pathway during the effector CD8 T cell response elicited after immunization with CD134 and CD137 costimulatory agonists. ST2 is rapidly up-regulated on CD27+ effector CD8 T cells during the earliest phase of T cell re-activation, even before the up-regulation of other well-known T cell activation markers. Also, CD27+ST2+ CD8 T cells expressed increased cytokines compared to CD27-veST2+ CD8 T cells, and blockade of ST2 impeded the expression of those cytokines. Moreover, CD27+ST2+ CD8 T cells can kill EL4 tumor targets. Thus, ST2 seems to be marking effector CD8 T cells with the best capacity to exert effector functions. Upon TCR engagement, viable effector CD8 T cells rapidly up-regulate ST2, which facilitates the delivery of additional activation signals through IL-33 that further augment T cell activation. Based on these findings, we hypothesize that IL-33 may be one of the first signals that link T cell activation with the local stromal environment. Thus, direct targeting of the more highly functional ST2+ CD8 T cells may improve the outcome of T cell-based cancer immunotherapies.
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Cordero da Luz, Felipe Andrés, Ana Paula Lima Oliveira, Daniella Borges, Paula Cristina Brígido, and Marcelo José Barbosa Silva. "The Physiopathological Role of IL-33: New Highlights in Bone Biology and a Proposed Role in Periodontal Disease." Mediators of Inflammation 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/342410.
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Interleukin-33 (IL-33) is a recently described member of the IL-1 family. IL-33 acts as an alarmin, chemoattractant, and nuclear factor. ST2, a member of the Toll-like receptor/IL-1R superfamily, the receptor of IL-33, triggers a plethora of downstream effectors and leads the activation of NFK-B, leading the expression of several genes. IL-33 and ST2 are expressed in the majority of cell types, and the IL-33/ST2 axis has a role in immune response, bone homeostasis, and osteoclastogenesis. Several studies show opposite roles of IL-33 in osteoclastogenesis and the implication in bone biology. Few works studied the role of IL-33 in periodontal disease, but we hypothesize a possible role of IL-33 in periodontal disease and bone loss.
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Jovicic, Nemanja, Ilija Jeftic, Marina Miletic Kovacevic, Irena Tanaskovic, Nebojsa Arsenijevic, Miodrag L. Lukic, and Nada Pejnovic. "ST2 Deficiency Ameliorates High Fat Diet-Induced Liver Steatosis In BALB/c Mice." Serbian Journal of Experimental and Clinical Research 16, no. 1 (March 1, 2015): 9–20. http://dx.doi.org/10.1515/sjecr-2015-0002.
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ABSTRACTNon-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity, but the molecular mechanisms of liver steatosis and its progression to non-alcoholic steatohepatitis and fibrosis are incompletely understood. Immune reactivity plays an important role in the pathogenesis of NAFLD. The IL-33/ST2 axis has a protective role in adiposity and atherosclerosis, but its role in obesity-associated metabolic disorders requires further clarification. To investigate the unresolved role of IL-33/ST2 signalling in NAFLD, we used ST2-deficient (ST2-/-) and wild type (WT) BALB/c mice maintained on a high-fat diet (HFD) for 24 weeks. HFD-fed ST2-/- mice exhibited increased weight gain, visceral adipose tissue weight and triglyceridaemia and decreased liver weight compared with diet-matched WT mice. Compared with WT mice on an HFD, ST2 deletion significantly reduced hepatic steatosis, liver inflammation and fibrosis and downregulated the expression of genes related to lipid metabolism in the liver. The frequency of innate immune cells in the liver, including CD68+ macrophages and CD11c+ dendritic cells, was lower in HFD-fed ST2-/- mice, accompanied by lower TNFα serum levels compared with diet-matched WT mice. Less collagen deposition in the livers of ST2-/- mice on an HFD was associated with lower numbers of profibrotic CD11b+Ly6clow monocytes and CD4+IL-17+ T cells in the liver, lower hepatic gene expression of procollagen, IL-33 and IL-13, and lower serum levels of IL-33 and IL-13 compared with diet-matched WT mice.Our findings suggest that the IL-33/ST2 axis may have a complex role in obesity-associated metabolic disorders. Although it is protective in HFD-induced adiposity, the IL-33/ST2 pathway promotes hepatic steatosis, inflammation and fibrosis.
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Rasheed, Kashif, Ugo Moens, Benedetta Policastro, John Inge Johnsen, Virve Koljonen, Harri Sihto, Weng-Onn Lui, and Baldur Sveinbjørnsson. "The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma." International Journal of Molecular Sciences 23, no. 7 (March 28, 2022): 3702. http://dx.doi.org/10.3390/ijms23073702.
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Merkel cell polyomavirus (MCPyV) is a causal factor in Merkel cell carcinoma (MCC). The oncogenic potential is mediated through its viral oncoproteins large T-antigen (LT) and small T-antigen (sT). Cytokines produced by tumor cells play an important role in cancer pathogenesis, and viruses affect their expression. Therefore, we compared human cytokine and receptor transcript levels in virus positive (V+) and virus negative (V−) MCC cell lines. Increased expression of IL-33, a potent modulator of tumor microenvironment, was observed in V+ MCC cell lines when compared to V− MCC-13 cells. Transient transfection studies with luciferase reporter plasmids demonstrated that LT and sT stimulated IL-33, ST2/IL1RL1 and IL1RAcP promoter activity. The induction of IL-33 expression was confirmed by transfecting MCC-13 cells with MCPyV LT. Furthermore, recombinant human cytokine domain IL-33 induced activation of MAP kinase and NF-κB pathways, which could be blocked by a ST2 receptor antibody. Immunohistochemical analysis demonstrated a significantly stronger IL-33, ST2, and IL1RAcP expression in MCC tissues compared to normal skin. Of interest, significantly higher IL-33 and IL1RAcP protein levels were observed in MCC patient plasma compared to plasma from healthy controls. Previous studies have demonstrated the implication of the IL-33/STL2 pathway in cancer. Because our results revealed a T-antigens-dependent induction of the IL-33/ST2 axis, IL-33/ST2 may play a role in the tumorigenesis of MCPyV-positive MCC. Therefore, neutralizing the IL-33/ST2 axis may present a novel therapeutic approach for MCC patients.
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Mathews, Lisa, Brian Rosborough, Angus Thomson, and Heth Turnquist. "IL-33 directly supports the proliferation of suppressive, naturally-occurring regulatory T cells expressing the IL-33 receptor, ST2 (161.1)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 161.1. http://dx.doi.org/10.4049/jimmunol.188.supp.161.1.
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Abstract Overview: Both IL-33 and its receptor, ST2, have been ascribed T helper type-2 (Th2) response promoting capacities. However, IL-33 increases splenic CD4+ forkhead box P3 (Foxp3)+ regulatory T cells (Treg) and post-transplant IL-33 monotherapy mediates a Treg-dependent prolongation of experimental cardiac allograft survival. As such, we addressed whether IL-33 directly targets Treg to support their expansion or suppressive function. Methods: The ability of recombinant IL-33 to facilitate anti-CD3/CD28-stimulated proliferation of BALB/c St2+/+ or St2-/- CD4+ CD25+ T cells was compared to IL-2. Following stimulation, Treg phenotype was defined by flow cytometry and their capacity to suppress naive T cell proliferation determined in bead-based suppression assays. Results: Following 3-4 days of culture, both cytokines promoted significant Treg proliferation vs. CD3/CD28 stimulation alone. However, IL-33 facilitated the expansion of a population ST2+ Foxp3+ cells that were absent from IL-2-treated cultures. Both IL-2 and IL-33-exposed Treg cultures exhibited suppressive activity. Conclusions: We identify the previously unreported capacity of IL-33 for direct expansion of Treg. Also, our data reveal that ST2, in addition to being expressed on Th2 cells, is found on an IL-33-expanded subset of suppressive Treg. These findings have significant implications for the therapeutic use of IL-33 to expand Treg, -cells critically important to tolerance and organ allograft survival.
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Kuo, Chih-Feng, Wei-Yu Chen, Hai-Han Yu, Yu-Hsuan Tsai, Ya-Chu Chang, Chih-Peng Chang, and Nina Tsao. "IL-33/ST2 Axis Plays a Protective Effect in Streptococcus pyogenes Infection through Strengthening of the Innate Immunity." International Journal of Molecular Sciences 22, no. 19 (September 29, 2021): 10566. http://dx.doi.org/10.3390/ijms221910566.
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Group A Streptococcus (GAS) causes invasive human diseases with the cytokine storm. Interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) axis is known to drive TH2 response, while its effect on GAS infection is unclear. We used an air pouch model to examine the effect of the IL-33/ST2 axis on GAS-induced necrotizing fasciitis. GAS infection induced IL-33 expression in wild-type (WT) C57BL/6 mice, whereas the IL-33- and ST2-knockout mice had higher mortality rates, more severe skin lesions and higher bacterial loads in the air pouches than those of WT mice after infection. Surveys of infiltrating cells in the air pouch of GAS-infected mice at the early stage found that the number and cell viability of infiltrating cells in both gene knockout mice were lower than those of WT mice. The predominant effector cells in GAS-infected air pouches were neutrophils. Absence of the IL-33/ST2 axis enhanced the expression of inflammatory cytokines, but not TH1 or TH2 cytokines, in the air pouch after infection. Using in vitro assays, we found that the IL-33/ST2 axis not only enhanced neutrophil migration but also strengthened the bactericidal activity of both sera and neutrophils. These results suggest that the IL-33/ST2 axis provided the protective effect on GAS infection through enhancing the innate immunity.
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Pastille, Eva, Marie-Hélène Wasmer, Alexandra Adamczyk, Vivian P. Vu, Lukas F. Mager, Nhi Ngo Thi Phuong, Vittoria Palmieri, et al. "The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer." Mucosal Immunology 12, no. 4 (June 5, 2019): 990–1003. http://dx.doi.org/10.1038/s41385-019-0176-y.
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AbstractThe composition of immune infiltrates strongly affects the prognosis of patients with colorectal cancer (CRC). Interleukin (IL)-33 and regulatory T cells (Tregs) in the tumor microenvironment have been separately implicated in CRC; however their contribution to intestinal carcinogenesis is still controversial. Here, we reveal that IL-33 signaling promotes CRC by changing the phenotype of Tregs. In mice with CRC, tumor-infiltrating Tregs preferentially upregulate IL-33 receptor (ST2), and IL-33/ST2 signaling positively correlates with tumor number and size. Transcriptomic and flow cytometry analyses demonstrate that ST2 expression induces a more activated and migratory phenotype in FOXP3+ Tregs, which favors their accumulation in the tumor environment. Consequently, genetic ablation of St2 reduces Treg infiltration and concomitantly enhances the frequencies of effector CD8+ T cells, thereby restraining CRC. Mechanistically, IL-33 curtails IL-17 production by FOXP3+ Tregs and inhibits Th17 differentiation. In humans, numbers of activated ST2-expressing Tregs are increased in blood and tumor lesions of CRC patients, suggesting a similar mode of regulation. Together, these data indicate a central role of IL-33/ST2 signaling in shaping an immunosuppressive environment during intestinal tumorigenesis. Blockade of this pathway may provide a strategy to modulate the composition of CRC immune infiltrates.
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Ramirez-Carrozzi, Vladimir, Amy Dressen, Patrick Lupardus, Brian Yaspan, and Rajita Pappu. "Functional analysis of protective IL1RL1 variants associated with asthma risk (CCR6P.215)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 187.2. http://dx.doi.org/10.4049/jimmunol.194.supp.187.2.
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Abstract GWAS studies have identified polymorphisms in both IL33 and IL1RL1, the gene encoding ST2, the high affinity chain of the IL-33 receptor, that associate with asthma susceptibility. We identified amino acid changing variants in IL1RL1 associating with asthma incidence and found these SNPs to be protective from asthma risk in our study population. These variants result in coding changes to the intracellular region of ST2, which contains the TIR domain of the receptor that is critical for signaling downstream of IL-1 cytokine family and TLRs. Mutations or deletions to this region can inhibit ligand-induced responses. IL-33-mediated dimerization of ST2 and IL-1RAcP promotes TIR-TIR domain interaction and recruitment of the adaptor molecule MyD88 leading to AP-1 and NF-kB activation. IL-33 responses were diminished in cell lines expressing all 4 IL1RL1 missense variants. To further elucidate how this haplotype could affect IL-33 activity, we compared IL-33 activity and ST2 expression between donors carrying either haplotype. We observed reduced IL-33 mediated IL-8 secretion from purified blood eosinophils derived from individuals carrying the protective haplotype. We also observed greater soluble ST2 expression in these individuals. Our results provide a link between the genetic predisposition to asthma and IL-33 mediated responses. Given IL-33 promotes Th2 immunity, perturbations that diminish this response may provide protection from asthma risk.
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Qian, Yujing, and Meifen Zhang. "The Functional Roles of IL-33/ST2 Axis in Ocular Diseases." Mediators of Inflammation 2020 (August 18, 2020): 1–11. http://dx.doi.org/10.1155/2020/5230716.
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Interleukin-33 (IL-33), an important member of the IL-1 family, plays a pivotal role in regulating immune responses via combining with its receptor suppression of tumorigenicity 2 (ST2). We have already known IL-33/ST2 axis participates in the pathogenesis of various diseases, including liver diseases, renal diseases, and neurological diseases. Recently, emerging studies are indicating that IL-33/ST2 is also involved in a wide range of ocular diseases, such as allergic eye disease, keratitis and corneal regeneration, dry eye disease, uveitis, vitreoretinal diseases, and neuromyelitis optica spectrum disorder. In this review, we will summarize and discuss the current understanding about the functional roles of IL-33/ST2 in eyes, with an attempt to explore the possible study perspectives and therapeutic alternatives in the future.
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Hasan, Amal, Shihab Kochumon, Ebaa Al-Ozairi, Jaakko Tuomilehto, and Rasheed Ahmad. "Association between Adipose Tissue Interleukin-33 and Immunometabolic Markers in Individuals with Varying Degrees of Glycemia." Disease Markers 2019 (April 3, 2019): 1–16. http://dx.doi.org/10.1155/2019/7901062.
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Introduction. Interleukin-33 (IL-33), the ligand for the receptor ST2, is abundant in adipose tissue, including preadipocytes, adipocytes, and endothelial cells. The IL-33/ST2 axis is protective against obesity, insulin resistance, and type 2 diabetes (T2D) in animal models. We determined whether adipose tissue IL-33 was associated with glycated hemoglobin (HbA1c), as well as mediators of inflammation and immune regulation and beiging of adipose tissue, among individuals with varying degrees of glycemia. Materials and Methods. A total of 91 adults with normoglycemia, prediabetes, and T2D were included. After measuring their anthropometric and biochemical parameters, subcutaneous adipose tissue samples were isolated and mRNA expression of cytokines, chemokines, chemokine receptors, pattern recognition receptors, and mediators involved in beiging of adipose tissue were measured. Results. Adipose tissue IL-33 was inversely associated with HbA1c in individuals with normoglycemia and T2D but not in those with prediabetes and was inversely correlated with fasting plasma glucose in individuals with T2D and with a better glycemic control. IL-33-to-ST2 ratio was inversely correlated with HbA1c in individuals with normoglycemia but not in those with prediabetes or T2D. IL-33 was directly associated with ST2, CD302, fibrinogen-like protein 2 (FGL2), and PR domain containing 16 (PRDM16) but inversely correlated with chemokine (C-C motif) ligand (CCL) 7 and CCL8 in individuals with normoglycemia. Similarly, IL-33 was directly associated with ST2, CD302, FGL2, PRDM16, and, additionally, toll-like receptor (TLR) 3 and IL-12A in individuals with T2D. However, IL-33 was not associated with any of these mediators but was directly and strongly associated with TLR9 in individuals with prediabetes. Conclusions. IL-33 and/or IL-33/ST2 dynamics and biological functions may play a role in overall glycemia among humans and may represent a novel target by which glucose-lowering managements confer their beneficial effects.
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Shakerian, Leila, Hanieh Kolahdooz, Mitra Garousi, Vahideh Keyvani, Ramiar Kamal Kheder, Tola Abdulsattar Faraj, Esmaeil Yazdanpanah, and Seyed-Alireza Esmaeili. "IL-33/ST2 axis in autoimmune disease." Cytokine 158 (October 2022): 156015. http://dx.doi.org/10.1016/j.cyto.2022.156015.
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Vianello, Elena, Elena Dozio, Lorenza Tacchini, Luigi Frati, and Massimiliano Marco Corsi Romanelli. "ST2/IL-33 signaling in cardiac fibrosis." International Journal of Biochemistry & Cell Biology 116 (November 2019): 105619. http://dx.doi.org/10.1016/j.biocel.2019.105619.
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Liu, Boyi, Yan Tai, Satyanarayana Achanta, Melanie M. Kaelberer, Ana I. Caceres, Xiaomei Shao, Jianqiao Fang, and Sven-Eric Jordt. "IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy." Proceedings of the National Academy of Sciences 113, no. 47 (November 7, 2016): E7572—E7579. http://dx.doi.org/10.1073/pnas.1606608113.
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Poison ivy-induced allergic contact dermatitis (ACD) is the most common environmental allergic condition in the United States. Case numbers of poison ivy ACD are increasing due to growing biomass and geographical expansion of poison ivy and increasing content of the allergen, urushiol, likely attributable to rising atmospheric CO2. Severe and treatment-resistant itch is the major complaint of affected patients. However, because of limited clinical data and poorly characterized models, the pruritic mechanisms in poison ivy ACD remain unknown. Here, we aim to identify the mechanisms of itch in a mouse model of poison ivy ACD by transcriptomics, neuronal imaging, and behavioral analysis. Using transcriptome microarray analysis, we identified IL-33 as a key cytokine up-regulated in the inflamed skin of urushiol-challenged mice. We further found that the IL-33 receptor, ST2, is expressed in small to medium-sized dorsal root ganglion (DRG) neurons, including neurons that innervate the skin. IL-33 induces Ca2+ influx into a subset of DRG neurons through neuronal ST2. Neutralizing antibodies against IL-33 or ST2 reduced scratching behavior and skin inflammation in urushiol-challenged mice. Injection of IL-33 into urushiol-challenged skin rapidly exacerbated itch-related scratching via ST2, in a histamine-independent manner. Targeted silencing of neuronal ST2 expression by intrathecal ST2 siRNA delivery significantly attenuated pruritic responses caused by urushiol-induced ACD. These results indicate that IL-33/ST2 signaling is functionally present in primary sensory neurons and contributes to pruritus in poison ivy ACD. Blocking IL-33/ST2 signaling may represent a therapeutic approach to ameliorate itch and skin inflammation related to poison ivy ACD.
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Abd Rachman Isnadi, Mohammad Faruq, Voon Kin Chin, Roslaini Abd Majid, Tze Yan Lee, Maizaton Atmadini Abdullah, Ramatu Bello Omenesa, Zaid Osamah Ibraheem, and Rusliza Basir. "Critical Roles of IL-33/ST2 Pathway in Neurological Disorders." Mediators of Inflammation 2018 (2018): 1–9. http://dx.doi.org/10.1155/2018/5346413.
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Interleukin-33 (IL-33) is an IL-1 family member, which exhibits both pro- and anti-inflammatory properties solely based on the type of the disease itself. Generally, IL-33 is expressed by both endothelial and epithelial cells and mediates its function based on the interaction with various receptors, mainly with ST2 variants. IL-33 is a potent inducer for the Th2 immune response which includes defence mechanism in brain diseases. Thus, in this paper, we review the biological features of IL-33 and the critical roles of IL-33/ST2 pathway in selected neurological disorders including Alzheimer’s disease, multiple sclerosis, and malaria infection to discuss the involvement of IL-33/ST2 pathway during these brain diseases and its potential as future immunotherapeutic agents or for intervention purposes.
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Caselli, C., A. D'Amico, R. Ragusa, R. Caruso, T. Prescimone, M. Cabiati, S. Nonini, et al. "IL-33/ST2 Pathway and Classical Cytokines in End-Stage Heart Failure Patients Submitted to Left Ventricular Assist Device Support: A Paradoxic Role for Inflammatory Mediators?" Mediators of Inflammation 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/498703.
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Background. Inflammation is a critical process contributing to heart failure (HF). We hypothesized that IL-33/ST2 pathway, a new mechanism regulated during cardiac stress, may be involved in the functional worsening of end-stage HF patients, candidates for left ventricular assist device (LVAD) implantation, and potentially responsible for their outcome.Methods. IL-33, ST2, and conventional cytokines (IL-6, IL-8, and TNF-α) were determined in cardiac biopsies and plasma of 22 patients submitted to LVAD implantation (pre-LVAD) and compared with (1) control stable chronic HF patients on medical therapy at the moment of heart transplantation without prior circulatory support (HT); (2) patients supported by LVAD at the moment of LVAD weaning (post-LVAD).Results. Cardiac expression of ST2/IL-33 and cytokines was lower in the pre-LVAD than in the HT group. LVAD determined an increase of inflammatory mediators comparable to levels of the HT group. Only ST2 correlated with outcome indices after LVAD implantation.Conclusions. IL-33/ST2 and traditional cytokines were involved in decline of cardiac function of ESHF patients as well as in hemodynamic recovery induced by LVAD. IL-33/ST2 pathway was also associated to severity of clinical course. Thus, a better understanding of inflammation is the key to achieving more favorable outcome by new specific therapies.
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Zhou, Ju, Ting Zhuang, Peng Ma, Lidong Shan, Xiao-Dong Sun, Shan Gong, Jin Tao, Xian-Min Yu, and Xinghong Jiang. "MicroRNA-547-5p-mediated interleukin-33/suppressor of tumorigenicity 2 signaling underlies the genesis and maintenance of neuropathic pain and is targeted by the therapy with bone marrow stromal cells." Molecular Pain 16 (January 2020): 174480692093173. http://dx.doi.org/10.1177/1744806920931737.
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Interleukin-33 (IL-33)/suppressor of tumorigenicity 2 (ST2) signaling is known to promote inflammation and the genesis and maintenance of neuropathic pain. However, it remained mostly unknown how IL-33/ST2 signaling can be enhanced by neuropathic stimulations. Here, we report that the chronic constriction nerve injury (CCI)-induced increases in the expression of IL-33 and ST2 and a decrease in microRNA (miRNA)-547-5p not only in the dorsal root ganglia (DRG) but also in spinal dorsal horn (SDH) ipsilateral to the CCI. We found that increasing endogenous miRNA-547-5p by the intrathecal (i.t.) infusion of agomir-miR-547-5p did not produce any effect in naive rats but blocked the CCI-induced increases in the IL-33 and ST2, and pain sensitivity. The reducing endogenous miRNA-547-5p by the i.t. delivering antagomir-miR-547-5p into naive rats caused significant changes in IL-33 and ST2 expressions in both the DRG and SDH, and pain sensitivity, which were similar to those induced by the CCI. Since increasing IL-33 by the i.t. infusion of recombinant IL-33 produced no change in the expression of miR-547-5p, and the CCI still reduced miR-547-5p expression in rats with the IL-33 knockdown, we conclude that the reduction of miR-547-5p can be an upstream event leading to the enhancement of IL-33/ST2 signaling induced by the CCI. The intravenous application of bone marrow stromal cells (BMSCs) reduced the depression of miR-547-5p in both the DRG and SDH, and pain hypersensitivity produced by the CCI or antagomir-miR547-5p application. However, the BMSC effect was significantly occluded by the pretreatment with miR-547-5p agomir or the IL-33 knockdown, demonstrating a novel mechanism underlying the BMSC therapy.
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Chen, Wei-Yu, Jaewoo Hong, Joseph Gannon, Rahul Kakkar, and Richard T. Lee. "Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33." Proceedings of the National Academy of Sciences 112, no. 23 (May 4, 2015): 7249–54. http://dx.doi.org/10.1073/pnas.1424236112.
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Hypertension increases the pressure load on the heart and is associated with a poorly understood chronic systemic inflammatory state. Interleukin 33 (IL-33) binds to membrane-bound ST2 (ST2L) and has antihypertrophic and antifibrotic effects in the myocardium. In contrast, soluble ST2 appears to act as a decoy receptor for IL-33, blocking myocardial and vascular benefits, and is a prognostic biomarker in patients with cardiovascular diseases. Here we report that a highly local intramyocardial IL-33/ST2 conversation regulates the heart’s response to pressure overload. Either endothelial-specific deletion of IL33 or cardiomyocyte-specific deletion of ST2 exacerbated cardiac hypertrophy with pressure overload. Furthermore, pressure overload induced systemic circulating IL-33 as well as systemic circulating IL-13 and TGF-beta1; this was abolished by endothelial-specific deletion of IL33 but not by cardiomyocyte-specific deletion of IL33. Our study reveals that endothelial cell secretion of IL-33 is crucial for translating myocardial pressure overload into a selective systemic inflammatory response.
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Gombert, Jean-Marc, Anaïs Levescot, Stéphane Flamant, Florence Jacomet, Sara Basbous, Olivier Féraud, Marie-Laure Bonnet, et al. "Bcr/Abl-induced deregulation of the IL-33/ST2 pathway in CD34(+) progenitors from chronic myeloid leukemia patients (P6284)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 46.13. http://dx.doi.org/10.4049/jimmunol.190.supp.46.13.
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Abstract Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myeloid leukemia (CML) and resistance to imatinib mesylate (IM) treatment remain poorly investigated. Here, we report that CD34(+) progenitors from CML patients at diagnosis are selectively targeted by the cytokine/alarmin IL-33. Indeed, CML CD34(+) progenitors up-regulate their cell surface expression of the IL-33-specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(+) cells from healthy individuals. Moreover, ST2 overexpression is normalized following IM therapy, while IL-33 counteracts in-vitro IM-induced growth arrest in CML CD34(+) progenitors via re-activation of the STAT5 pathway. Clinically, CML is associated with high circulating levels of soluble ST2, commonly used as a functional signature of IL-33 signaling in vivo. Taken together, our results support the hypothesis that the IL-33/ST2 pathway facilitates Bcr/Abl-induced leukemogenesis and contributes to IM resistance in CML patients.
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Choi, Yeon-Sook, Hyun-Jung Choi, Jeong-Ki Min, Bo-Jeong Pyun, Yong-Sun Maeng, Hongryeol Park, Jihye Kim, Young-Myeong Kim, and Young-Guen Kwon. "Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production." Blood 114, no. 14 (October 1, 2009): 3117–26. http://dx.doi.org/10.1182/blood-2009-02-203372.
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Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is emerging as a new regulator of immune responses and inflammatory vascular diseases. Although IL-33 and its cognate receptor ST2 appear to be expressed in vascular cells, the precise role of IL-33 in the vasculature has not been determined. In this study, we report a novel role of IL-33 as a potent endothelial activator, promoting both angiogenesis and vascular permeability. IL-33 increased proliferation, migration, and morphologic differentiation of human endothelial cells, consistently with increased angiogenesis in vivo. IL-33 also increased endothelial permeability with reduced vascular endothelial–cadherin-facilitated cell–cell junctions in vitro and induced vascular leakage in mouse skin. These effects of IL-33 were blocked by knockdown of ST2. Ligation of IL-33 with ST2 rapidly increased endothelial nitric oxide (NO) production through TRAF6-mediated activation of phosphoinoside-3-kinase, Akt, and endothelial NO synthase. Moreover, pharmacologic or genetic blockage of endothelial NO generation resulted in the inhibition of angiogenesis and vascular hyperpermeability induced by IL-33. These data demonstrate that IL-33 promotes angiogenesis and vascular leakage by stimulating endothelial NO production via the ST2/TRAF6-Akt-eNOS signaling pathway. These findings open new perspectives for the role of IL-33 in the pathogenesis of angiogenesis-dependent and inflammatory vascular diseases.
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Reichenbach, Dawn K., Vincent Schwarze, Benjamin M. Matta, Victor Tkachev, Elisabeth Lieberknecht, Quan Liu, Brent H. Koehn, et al. "The IL-33/ST2 axis augments effector T-cell responses during acute GVHD." Blood 125, no. 20 (May 14, 2015): 3183–92. http://dx.doi.org/10.1182/blood-2014-10-606830.
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Key Points IL-33 and ST2 expression are increased post-conditioning and with GVHD, resulting in increased T-cell activation via the IL-33/ST2 axis. Infusion of ST2-Fc protein exploits sST2’s function as a negative regulator of acute GVHD inhibiting pro-inflammatory cytokines.
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Yang, Fuhan, Mingming Wen, Dayu Pan, Xian Lin, Jing Mo, Xueyi Dong, Shihan Liao, and Yuemei Ma. "IL-33/ST2 Axis Regulates Vasculogenic Mimicry via ERK1/2-MMP-2/9 Pathway in Melanoma." Dermatology 235, no. 3 (2019): 225–33. http://dx.doi.org/10.1159/000498857.
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Background: Melanoma, an extremely malignant form of cancer, poses a significant health risk. Vasculogenic mimicry (VM), blood vessels formed by tumor cells instead of endothelial cells, is an important factor for the rapid progression of melanoma. Interleukin (IL)-33 is an inflammatory factor commonly found in the tumor microenvironment and plays an important role in the progression of many tumors. IL-33 acts on immune cells and tumor cells through its receptor ST2. This study hypothesized that IL-33 directly affects the progression of melanoma. Objectives: This study was designed to investigate the effect of IL-33 on VM of melanoma and its potential mechanism of action. Methods: The expression of ST2 was evaluated in 66 cases of melanoma collected from human patients, and the differences were analyzed. In vitro experiments were conducted to study the effects of the IL-33/ST2 axis on cell migration and invasion and to elucidate possible mechanisms. Results: ST2 expression is associated with that of matrix metalloproteinase (MMP)-2 and VM in melanoma of patients. IL-33 increases the abilities of proliferation, migration and invasion of melanoma cells and VM tube formation through ST2. IL-33 induces the production of MMP-2/9 via ERK1/2 phosphorylation. Conclusion: IL-33 can directly act on melanoma cells and promote its development.
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Noel, Gregory, Muhammad Imran Arshad, Aveline Filliol, Valentine Genet, Michel Rauch, Catherine Lucas-Clerc, Agnès Lehuen, Jean-Philippe Girard, Claire Piquet-Pellorce, and Michel Samson. "Ablation of interaction between IL-33 and ST2+ regulatory T cells increases immune cell-mediated hepatitis and activated NK cell liver infiltration." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 2 (August 1, 2016): G313—G323. http://dx.doi.org/10.1152/ajpgi.00097.2016.
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The IL-33/ST2 axis plays a protective role in T-cell-mediated hepatitis, but little is known about the functional impact of endogenous IL-33 on liver immunopathology. We used IL-33-deficient mice to investigate the functional effect of endogenous IL-33 in concanavalin A (Con A)-hepatitis. IL-33−/− mice displayed more severe Con A liver injury than wild-type (WT) mice, consistent with a hepatoprotective effect of IL-33. The more severe hepatic injury in IL-33−/− mice was associated with significantly higher levels of TNF-α and IL-1β and a larger number of NK cells infiltrating the liver. The expression of Th2 cytokines (IL-4, IL-10) and IL-17 was not significantly varied between WT and IL-33−/− mice following Con A-hepatitis. The percentage of CD25+ NK cells was significantly higher in the livers of IL-33−/− mice than in WT mice in association with upregulated expression of CXCR3 in the liver. Regulatory T cells (Treg cells) strongly infiltrated the liver in both WT and IL-33−/− mice, but Con A treatment increased their membrane expression of ST2 and CD25 only in WT mice. In vitro, IL-33 had a significant survival effect, increasing the total number of splenocytes, including B cells, CD4+ and CD8+ T cells, and the frequency of ST2+ Treg cells. In conclusion, IL-33 acts as a potent immune modulator protecting the liver through activation of ST2+ Treg cells and control of NK cells.
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Wierzbicka, Justyna M., Anna Piotrowska, Dorota Purzycka-Bohdan, Anna Olszewska, Joanna I. Nowak, Aneta Szczerkowska-Dobosz, Bogusław Nedoszytko, Roman J. Nowicki, and Michał A. Żmijewski. "The Effects of Vitamin D on the Expression of IL-33 and Its Receptor ST2 in Skin Cells; Potential Implication for Psoriasis." International Journal of Molecular Sciences 22, no. 23 (November 29, 2021): 12907. http://dx.doi.org/10.3390/ijms222312907.
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Interleukin 33 (IL-33) belongs to the IL-1 family and is produced constitutively by epithelial and endothelial cells of various organs, such as the skin. It takes part in the maintenance of tissue homeostasis, repair, and immune response, including activation of Th2 lymphocytes. Its involvement in pathogenesis of several inflammatory diseases including psoriasis was also suggested, but this is not fully understood. The aim of the study was to investigate expression of IL-33 and its receptor, ST2, in psoriasis, and the effects of the active form of vitamin D (1,25(OH)2D3) on their expression in skin cells. Here we examined mRNA and protein profiles of IL-33 and ST2 in 18 psoriatic patients and healthy volunteers by qPCR and immunostaining techniques. Potential effects of 1,25(OH)2D3 and its receptor (VDR) on the expression of IL-33 and ST2 were tested in cultured keratinocytes, melanocytes, fibroblasts, and basal cell carcinoma cells. It was shown that 1,25(OH)2D3 effectively stimulated expression of IL-33 and its receptor ST2’s mRNAs in a time-dependent manner, in keratinocytes and to the lesser extends in melanocytes, but not in fibroblasts. Furthermore, the effect of vitamin D on expression of IL-33 and ST2 was VDR-dependent. Finally, we demonstrated that the expression of mRNA for IL-33 was mainly elevated in the psoriatic skin but not in its margin. Interestingly, ST2 mRNA was downregulated in psoriatic lesion compared to both marginal tissue as well as healthy skin. Our data indicated that vitamin D can modulate IL-33 signaling, opening up new perspectives for our understanding of the mechanism of vitamin D action in psoriasis therapy.
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Leal-Silva, Thaís, Flaviane Vieira-Santos, Fabrício Marcus Silva Oliveira, Luiza de Lima Silva Padrão, Lucas Kraemer, Pablo Hemanoel da Paixão Matias, Camila de Almeida Lopes, et al. "Detrimental role of IL-33/ST2 pathway sustaining a chronic eosinophil-dependent Th2 inflammatory response, tissue damage and parasite burden during Toxocara canis infection in mice." PLOS Neglected Tropical Diseases 15, no. 7 (July 29, 2021): e0009639. http://dx.doi.org/10.1371/journal.pntd.0009639.
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Toxocariasis is a neglected disease that affects people around the world. Humans become infected by accidental ingestion of eggs containing Toxocara canis infective larvae, which upon reaching the intestine, hatch, penetrate the mucosa and migrate to various tissues such as liver, lungs and brain. Studies have indicated that Th2 response is the main immune defense mechanism against toxocariasis, however, there are still few studies related to this response, mainly the IL-33/ST2 pathway. Some studies have reported an increase in IL-33 during helminth infections, including T. canis. By binding to its ST2 receptor, IL-33 stimulating the Th2 polarized immune cell and cytokine responses. Thus, we aimed to investigate the role of the IL-33/ST2 pathway in the context of T. canis larval migration and the immunological and pathophysiological aspects of the infection in the liver, lungs and brain from Wild-Type (WT) BALB/c background and genetically deficient mice for the ST2 receptor (ST2-/-). The most important findings revealed that the IL-33/ST2 pathway is involved in eosinophilia, hepatic and cerebral parasitic burden, and induces the formation of granulomas related to tissue damage and pulmonary dysfunction. However, ST2-/- mice, the immune response was skewed to Th1/Th17 type than Th2, that enhanced the control of parasite burden related to IgG2a levels, tissue macrophages infiltration and reduced lung dysfunction. Collectively, our results demonstrate that the Th2 immune response triggered by IL-33/ST2 pathway mediates susceptibility to T. canis, related to parasitic burden, eosinophilia and granuloma formation in which consequently contributes to tissue inflammation and injury.
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Wang, Jun-Xia, Shinjiro Kaieda, and Peter Nigrovic. "IL-33/ST2 promotes tissue mastocytosis under conditions of inflammation (CCR3P.219)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 115.16. http://dx.doi.org/10.4049/jimmunol.192.supp.115.16.
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Abstract Mast cells (MC) are potent innate immune cells that accumulate in chronically inflamed tissues, where they have been implicated in multiple allergic and inflammatory diseases. MC express the IL-33 receptor ST2, and this new member of the IL-1 cytokine family is recognized as an important pathway both for direct MC activation and for priming MC to respond to other pro-inflammatory signals. However, IL-33 has no known role in tissue mastocytosis. Using primary MC cultured from human skin, we found that IL-33 did not alter MC proliferation but instead protected MC from apoptosis, principally through upregulation of the anti-apoptotic molecule BCLXL. Murine bone marrow-derived MC demonstrated a similar response to IL-33, dependent entirely upon ST2, allowing us to test the role of this biology in vivo. Mice lacking ST2 exhibited fewer peritoneal MC as well as reduced accumulation of MC in inflamed arthritic joints and helminth-infected intestine. Upon engraftment into the peritoneum, WT MC exhibited a clear, IL-33-mediated survival advantage over ST2-deficient MC, in particular after thioglycollate-induced peritonitis. Together, these data reveal a novel, cell-intrinsic role for the IL-33/ST2 axis in tissue mastocytosis, especially under conditions of local inflammation.
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Johnston, Laura, Sergejs Berdnikovs, Rebecca Krier-Burris, Chia-Lin Hsu, Karen Chien, and Paul Bryce. "IL-33 precedes IL-5 in regulating early commitment to eosinophil development (HEM5P.229)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 120.9. http://dx.doi.org/10.4049/jimmunol.194.supp.120.9.
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Abstract IL-33 is strongly associated with allergic disease, in part because of the potent effects it exerts on Th2 lymphocytes, ILC2s, mast cells, and eosinophils, which express its receptor ST2. However, ST2 has also recently been observed on hematopoietic progenitor cells. The effect of IL-33 on these cells is unclear. We observed that naïve ST2KO and IL-33KO mice had significantly less peripheral blood eosinophils (PBEs), whereas exogenous IL-33 was sufficient to elevate PBEs in WT and IL-33KO mice, but not in ST2KO mice. This was associated with increased myeloid/erythroid cell ratios in the bone marrow itself. IL-33 treatment expanded a Sca1-/Linint/SiglecF+ population, characteristic of a committed eosinophil progenitor. Using in vitro eosinophilopoesis conditions, IL-33 promoted mature eosinophil commitment (Sca1-/Lin+/SiglecF+) that was significantly diminished in ST2KO cells. Instead, ST2KO cells accumulated a Sca1-/Lin-/SiglecF+ population, characteristic of an early committed precursor. In contrast, IL-5, which has been shown to drive eosinophil development, expanded mature eosinophils. Finally, we assessed the hierarchy of IL-5 and IL-33 by crossing IL-5 overexpressing transgenic mice (NJ1638) with ST2KO mice. While IL-5 transgenic mice exhibited a robust age-dependent increase in PBEs, ST2 deficiency significantly prevented this IL-5-driven eosinophilia. Our findings demonstrate a novel role for IL-33 and ST2 in supporting eosinophil development that precedes IL-5.
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Zoltowska Nilsson, A. M., Y. Lei, M. Adner, and G. P. Nilsson. "Mast cell-dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma." American Journal of Physiology-Lung Cellular and Molecular Physiology 314, no. 3 (March 1, 2018): L484—L492. http://dx.doi.org/10.1152/ajplung.00270.2017.
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Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated with the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. Mast cell-deficient C57BL/6-KitW-sh (Wsh) mice engrafted with either wild-type (Wsh + MC-WT) or ST2-deficient bone marrow-derived mast cells (Wsh + MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh + MC-ST2KO compared with Wsh + MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in bronchoalveolar lavage fluid (BALF) and lung, the aggravated AHR in Wsh + MC-ST2KO mice seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE2 levels in BALF. Due to the protective properties of PGE2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role, in the development of AHR.
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Pan, Xiaolan, Meiqin Li, Lei Huang, Dan Mo, Yihua Liang, Zhaodong Huang, Bo Zhu, Min Fang, and Ernesto S. Nakayasu. "CD44, IL-33, and ST2 Gene Polymorphisms on Hepatocellular Carcinoma Susceptibility in the Chinese Population." BioMed Research International 2020 (September 29, 2020): 1–11. http://dx.doi.org/10.1155/2020/2918517.
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The interleukin- (IL-) 33/ST2 axis plays a pivotal role in tumorigenesis through influencing cancer stemness and other mechanisms. CD44 is one of the critical markers of hepatocellular carcinoma (HCC) among the cancer stem cells (CSCs). There is still a lack of CD44 gene single-nucleotide polymorphisms (SNPs) combined with IL-33/ST2 pathway single-nucleotide polymorphisms in HCC susceptibility analysis literature, although CD44 and IL-33/ST2 have been reported separately in human cancers. This study is aimed at investigating the relationship between CD44, IL-33, and ST2 SNPs and HCC susceptibility and clinicopathological features. We analyzed 565 HCC patients and 561 healthy controls in the Chinese population. The genes for CD44rs187115A>G, IL-33 rs1929992A>G, and ST2 rs3821204G>C were typed using the SNaPshot method. We found that the distribution frequencies of CD44 and ST2 alleles and genotypes in both the HCC case group and the control group were statistically significant ( p < 0.05 ). The results showed that individuals carrying at least one G allele of the CD44 rs187115 gene were at a higher risk than the AA genotype carriers ( p = 0.007 , odds ratio OR = 1.429 , 95% confidence interval (CI): 1.102–1.854). Similarly, individuals with at least one C allele of ST2 rs3821204 had a higher risk of HCC than those with GG genes ( p ≤ 0.001 , OR = 1.647 , 95% CI: 1.296-2.093). Combining the haplotype analysis of the 3 loci suggested that CD44 rs187115, IL-33 rs1929992, and ST2 rs3821204 are associated with the risk of HCC and could potentially serve as useful genetic markers for HCC in some populations of China.