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Role of IL-33 in inflammation and disease

Ashley M Miller

Journal of Inflammation · 2011 · Review

Abstract

Interleukin (IL)-33 is a new member of the IL-1 superfamily of cytokines that is expressed by mainly stromal cells, such as epithelial and endothelial cells, and its expression is upregulated following pro-inflammatory stimulation. IL-33 can function both as a traditional cytokine and as a nuclear factor regulating gene transcription. It is thought to function as an 'alarmin' released following cell necrosis to alerting the immune system to tissue damage or stress. It mediates its biological effects via interaction with the receptors ST2 (IL-1RL1) and IL-1 receptor accessory protein (IL-1RAcP), both of which are widely expressed, particularly by innate immune cells and T helper 2 (Th2) cells. IL-33 strongly induces Th2 cytokine production from these cells and can promote the pathogenesis of Th2-related disease such as asthma, atopic dermatitis and anaphylaxis. However, IL-33 has shown various protective effects in cardiovascular diseases such as atherosclerosis, obesity, type 2 diabetes and cardiac remodeling. Thus, the effects of IL-33 are either pro- or anti-inflammatory depending on the disease and the model. In this review the role of IL-33 in the inflammation of several disease pathologies will be discussed, with particular emphasis on recent advances.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Basic Biology of IL-33

1Interleukin (IL)-33 (also known as IL-1F11) was originally identified as DVS27, a gene up-regulated in canine cerebral vasospasm, and as "nuclear factor from high endothelial venules" (NF-HEV). However, in 2005 analysis of computational structural databases revealed that this protein had close amino acid homology to IL-18, and a β-sheet trefoil fold structure characteristic of IL-1 family members. IL-33 binds to a ST2L (also known as T1, IL-1RL1, DER4), which is a member of the Toll-like receptor (TLR)/IL1R superfamily. IL-33/ST2L then forms a complex with the ubiquitously expressed IL-1R accessory protein (IL-1RAcP). Signaling is induced through the cytoplasmic Toll-interleukin-1 receptor (TIR) domain of IL-1RAcP. This leads to recruitment of the adaptor protein MyD88 and activation of transcription factors such as NF-κB via TRAF6, IRAK-1/4 and MAP kinases and the production of inflammatory mediators (Figure 1). The ST2 gene can also encode at least 2 other isoforms in addition to ST2L by alternative splicing, including a secreted soluble ST2 (sST2) form which can serve as a decoy receptor for IL-33, and an ST2V variant form present mainly in the gut of humans. Signaling through ST2L also appears to be negatively regulated by the molecule single Ig IL-1R-related molecule (SIGIRR) and IL-33 induced immune responses were enhanced in SIGIRR-/- mice.

2IL-33 appears to be a cytokine with dual function, acting both as a traditional cytokine through activation of the ST2L receptor complex and as an intracellular nuclear factor with transcriptional regulatory properties. The amino terminus of the IL-33 molecule contains a nuclear localization signal and a homeodomain (helix-turn-helix-like motif) that can bind to heterochromatin in the nucleus and has similar structure to the Drosophila transcription factor engrailed. In a similar manner to which a motif found in Kaposi sarcoma herpesvirus LANA (latency-associated nuclear antigen) attaches its viral genomes to mitotic chromosomes, nuclear IL-33 is thought to be involved in transcriptional repression by binding to the H2A-H2B acidic pocket of nucleosomes and regulating chromatin compaction by promoting nucleosome-nucleosome interactions. However, the specific transcriptional targets or the biological effects of nuclear IL-33 are unclear at present.

3Both IL-1β and IL-18 are synthesized as a biologically inactive precursors and activated by caspase-1 cleavage under pro-inflammatory conditions and it was initially thought that IL-33 underwent similar processing by caspase-1. However, recent studies suggest that proteolytic processing is not required for IL-33 signaling via ST2L. Furthermore, it has been suggested that a new splice variant of IL-33 exists, which lacks the putative caspase-1 cleavage site, and is biologically active inducing signaling via ST2L. In fact, cleavage of IL-33 by caspases appears to mediate inactivation of IL-33 and its pro-inflammatory properties. Currently, it is thought that full length biologically active IL-33 may be released during necrosis as a endogenous danger signal or 'alarmin', but during apoptosis IL-33 is cleaved by caspases leading to inactivation of its pro-inflammatory properties.

IL-33, an inducer of Th2 immune responses

4Unlike the other IL-1 family members IL-33 primarily induces T helper 2 (Th2) immune responses in a number of immune cell types (reviewed in detail in). ST2L was initially shown to be selectively expressed on Th2, but not Th1 or regulatory (Treg) T cells. Subsequent studies have shown that IL-33 can activate murine dendritic cells directly driving polarization of naïve T cells towards a Th2 phenotype, and it can act directly on Th2 cells to increase secretion of Th2 cytokines such as IL-5 and IL-13. Furthermore, IL-33 can also act as a chemo-attractant for Th2 cells. IL-33 can activate B1 B cells in vivo, markedly enhancing production of IgM antibodies and IL-5 and IL-13 production from these cells.

5IL-33 is also a potent activator of the innate immune system. Schmitz and co-workers demonstrated that injection of IL-33 into mice induces a profound eosinophilia, and has potent effects on this cell type, including induction of superoxide anion and IL-8 production, degranulation and cell survival. Subsequently, it has been shown that IL-33 is also a potent activator of mast cells and basophils and can induce degranulation, maturation, promote survival and the production of several pro-inflammatory cytokines in these cells. In neutrophils, IL-33 prevents the down-regulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4. Macrophages constitutively express ST2L and IL-33 can amplify an IL-13-driven polarization of macrophages towards an alternatively activated or M2 phenotype, thus enhancing Th2 immune responses. IL-33 can also enhance LPS-induced production of TNFα in these cells.

6It is likely that the primary role of these IL-33 effects on the immune system in evolutionary terms was in host defense against pathogens. In fact, IL-33/ST2 have been shown to be highly expressed and protective several parasite infections in animal models in which Th2 cells are host protective, including Leishmania major, Toxoplasma gondii, Trichuris muris, and Nippostrongylus brasiliensis. Furthermore, a recent discovery has highlighted a new population of cells named nuocytes which expand in response to IL-33 and represent the predominant early source of IL-13 during helminth infection with Nippostrongylus brasiliensis. However, it is clear that the potent activatory effects of IL-33 on several immune cell types is likely to impact on various inflammatory diseases.

Asthma

7Asthma is a chronic inflammatory disease classically characterized by airway hyper-responsiveness, allergic inflammation, elevated serum IgE levels, and increased Th2 cytokine production. Given that IL-33 is a strong inducer of Th2 immune responses its role in asthma has been extensively studied (reviewed in). Initial gene expression studies in a range of tissues using human and mouse cDNA libraries revealed expression of IL-33 in lung tissue, and high expression in bronchial smooth muscle cells. More recently, expression of IL-33 was found in higher levels in endobronchial biopsies from human asthmatic subjects compared to controls. The IL-33 expression was particularly evident in those with severe asthma, and the expression was mainly located in bronchial epithelial cells. Studies to investigate which cells were the main IL-33 responsive cells in lung demonstrated that both epithelial and endothelial cells, but not smooth muscle cells or fibroblasts were important. Several animal model studies have highlighted a functionally important role for IL-33/ST2 in asthma and allergic airways inflammation. In a murine ovalbumin-induced airway inflammation model, intranasal administration of IL-33 induces antigen-specific IL-5+ T cells and promotes allergic airway disease even in the absence of IL-4. Furthermore, intranasal IL-33 also promotes airways hyper-responsiveness, goblet cell hyperplasia, eosinophilia, polarization of macrophages towards an M2 phenotype, and accumulation of lung IL-4, IL-5 and IL-13. More recently, an IL-33 transgenic mouse was generated in which IL-33 expression was controlled under a CMV promoter and released as a cleaved 18 kDa protein in pulmonary tissue. These mice developed massive airway inflammation with infiltration of eosinophils, hyperplasia of goblet cells and accumulation of pro-inflammatory cytokines in bronchoalveolar lavage fluid. In contrast, intraperitoneal anti-IL-33 antibody treatment inhibited allergen-induced lung eosinophilic inflammation and mucus hypersecretion in a murine model. Furthermore, administration of blocking anti-ST2 antibodies or ST2-Ig fusion protein inhibited Th2 cytokine production in vivo, eosinophilic pulmonary inflammation and airways hyper-responsiveness. At present, the role of IL-33/ST2 in studies using ST2-deficient mice is unclear as these mice are not protected in the ovalbumin-induced airway inflammation model but have attenuated inflammation in a short-term priming model of asthma. Furthermore, there is also an exacerbation of disease in wild-type or Rag-1-/- mice that had undergone adoptive transfer of ST2-/- DO11.10 Th2 cells. In order to clarify the role of IL-33/ST2 in lung inflammation, several groups have generated mice deficient in IL-33. Oboki and co-workers demonstrated that 2 sensitizations of IL-33-/- mice with ovalbumin emulsified in alum showed attenuated eosinophil and lymphocyte recruitment to the lung, airway hyper-responsiveness and inflammation. A similar study by Louten and colleagues has also shown that endogenous IL-33 contributes to airway inflammation and peripheral antigen-specific responses in ovalbumin-induced acute allergic lung inflammation using IL-33-/- mice. Collectively, the data suggest that IL-33 is involved in lung inflammation and supports the concept of ST2 as a therapeutic target in asthma.

Rheumatological diseases

8Recent evidence suggests a role for IL-33/ST2 in several rheumatological diseases, including rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA) and systemic lupus erythematosus (SLE). The first study to link IL-33 expression with arthritis utilized in situ hybridization to show that IL-33 mRNA expression in the RA synovium is primarily in endothelial cells. Subsequently, IL-33 protein has been found in endothelial cells of synovial tissue and in cells morphologically consistent with synovial fibroblasts in a subset of RA, PsA and OA patients. IL-33 is also expressed in cultured synovial fibroblasts from patients with RA and expression was markedly elevated in vitro by inflammatory cytokines. Circulating IL-33 protein has also been detected in 94/223 RA patient serum samples by ELISA, but was completely absent in healthy controls or OA samples. Furthermore, the level of serum IL-33 decreased after anti-TNF treatment and correlated with production of IgM and RA-related autoantibodies including Rheumatoid Factor and anti-citrullinated protein antibodies. Serum and synovial fluid levels of IL-33 have also been shown to decrease in patients who respond to anti-TNF treatment, while they did not change in non-responders. Similarly, Talabot-Ayer and co-workers show that serum and synovial fluid IL-33 levels were higher in RA than in OA patients, and undetectable in PsA serum and synovial fluid. Another study has demonstrated that neutrophils from patients with RA successfully treated with anti-TNF treatment expressed significantly lower levels of ST2 than patients treated with methotrexate alone. In SLE, one study has shown serum IL-33 levels were significantly increased, compared with healthy controls, but to a lower extent than in patients with RA. The other study reported no change in serum IL-33 levels between controls and SLE patients, but did report a significant increase in sST2 that correlated with SLE disease activity.

9In murine models of RA, IL-33 mRNA has also been detected in the joints of mice undergoing collagen-induced arthritis (CIA), and in mouse knee joints injected with methylated bovine serum albumin. Furthermore, ST2-/- mice developed attenuated CIA and reduced ex vivo collagen-specific induction of pro-inflammatory cytokines (IL-17, TNFα, and IFNγ), and antibody production. Conversely, treatment with IL-33 exacerbated CIA and elevated production of both pro-inflammatory cytokines and anti-collagen antibodies through a mast cell-dependent pathway. Administration of blocking anti-ST2 antibodies at the onset of CIA also attenuated the severity of disease and reduced joint destruction. This was also associated with reduced IFNγ and IL-17 production. In a model of anti-glucose-6-phosphate isomerase autoantibody-induced arthritis, IL-33 treatment exacerbated disease. Conversely, ST2-/- mice were protected against disease and had reduced expression of articular pro-inflammatory cytokines. The IL-33 effects in this model also appear to be mast cell-dependent as IL-33 failed to increase the severity of the disease in mast cell-deficient mice, and mast cells from wild-type, but not ST2-/- mice restored the ability of ST2-/- recipients to respond. IL-33 has also been shown to chemoattract neutrophils to a knee joint injected with methylated bovine serum albumin.

10Various rheumatological diseases can have effects on bone including erosion (e.g. RA) and ossification and the formation of new bone (e.g., ankylosing spondylitis and OA). Recently, the role of IL-33 in bone metabolism and remodeling has been studied with conflicting results. Bone structure and metabolism are determined by the formation and activity of osteoclasts and osteoblasts. Mun and co-workers showed that IL-33 can stimulate the formation of multi-nuclear osteoclasts from monocytes, and enhanced expression of osteoclast differentiation factors including TRAF6, nuclear factor of activated T cells cytoplasmic 1, c-Fos, c-Src, cathepsin K, and calcitonin receptor. However, in contrast two other studies have shown that IL-33 completely abolished the generation of multinucleated osteoclasts or had no direct effect.

11IL-33 also appears to have direct effects on osteoblast cells. IL-33 expression increases during osteoblast differentiation, and that while ST2-/- mice displayed normal bone formation they had increased bone resorption, thereby resulting in low trabecular bone mass. Furthermore, IL-33 mRNA levels are increased in osteoblasts following treatment with the bone anabolic factors parathyroid hormone or oncostatin M. In addition, IL-33 treatment promoted matrix mineral deposition by osteoblasts in vitro. However, a recent study reports conflicting data that while IL-33 mRNA is present in human osteoblasts, ST2L is not constitutively expressed and IL-33 treatment has no effect on these cells. The reasons for these differences in the biology of IL-33 in osteoclasts and osteoblasts are unclear at present but may reflect different cell culture conditions and differentiation protocols used. In summary, IL-33 appears to have pro-inflammatory effects in various rheumatological diseases activating synovial fibroblasts and mast cells within joints.

Inflammatory skin disorders

12Skin and activated dermal fibroblasts contain a high level of IL-33 mRNA expression compared to other tissues and cell types. IL-33 mRNA and protein is also substantially higher in the skin lesions of patients with atopic dermatitis compared with non-inflamed skin samples, and in affected psoriatic skin compared to healthy skin. Elevated serum IL-33 levels have also been detected in patients with systemic sclerosis, and levels correlated positively with the extent of skin sclerosis. Furthermore, subcutaneous administration of IL-33 can induce IL-13-dependent fibrosis of skin in murine models. Recently, it was shown that ST2-/- mice exhibited reduced cutaneous inflammatory responses compared to WT mice in a phorbol ester-induced model of skin inflammation. Furthermore, intradermal injections of IL-33 into the ears of mice induced a psoriasis-like inflammatory lesion that was partially dependent on mast cells.

13In addition, IL-33 expression was induced in pericytes in an experimental model of wound healing in rat skin. Surprisingly, IL-33 has also been shown to induce cutaneous hypernociception in mice, a phenomenon traditionally associated with Th1 responses. Collectively, these results demonstrate that IL-33 may play a role in various inflammatory skin disorders (Figure 2).

Inflammatory bowel disease (IBD)

14IBD is a group of chronic inflammatory conditions of the colon and small intestine, including ulcerative colitis (UC) and Crohn's disease, resulting from dysregulated immune responses. Several studies report an upregulation of IL-33 mRNA in human biopsy specimens from untreated or active UC patients compared to controls. The main sites of UC IL-33 expression were myofibroblasts and epithelial cells. Similarly, ST2 transcripts have been detected in mucosa samples from patients with active UC. However, although Carriere and co-workers demonstrated expression of IL-33 in endothelial cells of Crohn's disease intenstine, subsequent studies have failed to demonstrate a significant role for IL-33 in Crohn's disease. Serum IL-33 and sST2 levels were elevated in UC patients compared with controls, while anti-TNF treatment decreased circulating IL-33 and increased sST2, thus favorably altering the ratio of the cytokine with its decoy receptor. However, in other studies serum concentrations of IL-33 were low or did not differ between UC patients and healthy controls.

15Several murine studies highlight a role for IL-33 in innate-type immunity in the gut. Mice treated with IL-33 displayed epithelial hyperplasia and eosinophil/neutrophil infiltration in the colonic mucosa. Furthermore, in a murine model of T-cell independent dextran sodium sulphate (DSS)-induced colitis IL-33-/- mice had enhanced viability, compared to wild-type controls. In a related study macrophage-specific transgenic mice that express a truncated TGF-β receptor II under control of the CD68 promoter (CD68TGF-βDNRII) and subjected to the DSS model of colitis display an impaired ability to resolve colitic inflammation but also an increase in IL-33+ macrophages compared to controls. In addition, IL-33 mRNA is upregulated in the ilea and correlates with disease severity in a murine model of Th1/Th2-mediated enteritis, and induced IL-17 production from mesenteric lymph node cells stimulated ex vivo. In summary, the IL-33/ST2 pathway may be an important regulator of UC, but be of less importance in Crohn's disease.

Central nervous system (CNS) inflammation

16Basal IL-33 mRNA levels are extremely high in the brain and spinal cord, and are elevated under conditions such as experimental subarachnoid hemorrhage. Furthermore, expression of IL-33 in glial and astrocyte cultures is increased by Toll-like receptor ligands. Treatment with IL-33 induces proliferation of microglia and enhances production of pro-inflammatory cytokines, such as IL-1β and TNFα, as well as the anti-inflammatory cytokine IL-10. It also enhances chemokines and nitric oxide production and phagocytosis by microglia. In mice, IL-33 levels and activity were increased in brains infected with the neurotropic virus Theiler's murine encephalomyelitis virus. Finally, a transcriptional analysis of brain tissue from patients with Alzheimer's disease revealed that IL-33 expression was decreased compared to control tissues. This study also demonstrated that 3 polymorphisms within the IL-33 gene resulting in a protective haplotype were associated with risk of Alzheimer's disease. This data is supported by a study in Chinese population with evidence that genetic variants of IL-33 affect susceptibility to Alzheimer's disease. Furthermore, cell-based assays demonstrate that IL-33 can decrease secretion of β-amyloid peptides. Thus, IL-33 may have a role in regulating pathophysiology and inflammatory responses in the CNS.

Cancer

17Although early reports document the expression of ST2 on leukaemic cell lines and on T cell lymphomas of patients, very few studies have addressed the role of IL-33/ST2 signaling on anti-tumor immune responses, tumor growth and/or metastasis. However, a recent study demonstrated that ST2-/- mice with mammary tumors have attenuated tumor growth and metastasis, with increased circulating levels of pro-inflammatory cytokines and activated NK and CD8+ T cells. Furthermore, IL-33 induces proliferation, migration, and morphologic differentiation of endothelial cells, consistent with an effect on angiogenesis. In addition, IL-33 expression is present in endothelial cells of healthy organs but is strikingly absent from those in tumors. Therefore, IL-33 may be an important mediator in tumor escape from immune control and in tumor angiogenesis and thus warrants further investigation.

Cardiovascular (CV) disease

18IL-33 was initially found in the nucleus of the high endothelial venules (HEV) of secondary lymphoid tissues. More recently, IL-33 expression has been reported in coronary artery smooth muscle cells, coronary artery endothelium, non-HEV endothelial cells, adipocytes, and in cardiac fibroblasts suggesting that IL-33 may play a role in various CV disorders.

sST2 as a CV biomarker

19This concept is supported by the clinical finding that the IL-33 decoy receptor sST2 was elevated in serum early after acute myocardial infarction (AMI), and correlated with creatine kinase and inversely correlated with left ventricular ejection fraction. Since this primary observation several studies have since demonstrated the prognostic value of measuring serum sST2 in various CV diseases, showing that high baseline levels of sST2 were a significant predictor of CV mortality and heart failure (HF) (Table 1). Taken together, these studies indicate that sST2 has the potential to be a predictive CV biomarker in patients with AMI, HF and dyspnea. Thus far, serum or plasma IL-33 has not been measured in CV disease. While levels are elevated in atopy, and some rheumatological diseases, the levels in CV disease are likely to be low (possibly due to elevated sST2 levels) and difficult to measure with currently available assays. However, recent studies have highlighted the development of multiplex assays to measure low abundance IL-33 in serum or plasma and warrant further investigation in the context of CV disease. In summary, sST2 shows promise as a biomarker predictive of mortality in several CV disorders.

Cardiac fibrosis and hypertrophy

20Studies in animal models suggest that sST2 is more than just a marker in CV disease and implicate IL-33/ST2 signaling as an important protective pathway in various CV diseases. In a model of pressure overload IL-33 treatment reduced cardiac hypertrophy and fibrosis, and improved survival following transverse aortic constriction in wild-type but not ST2-/- mice. Furthermore, sST2 blocked the anti-hypertrophic effects of IL-33, indicating that sST2 functions in the myocardium as a soluble decoy receptor of IL-33. IL-33 can also reduce cardiomyocyte apoptosis, decrease infarct and fibrosis, and improve ventricular function in vivo via suppression of caspase-3 activity and increased expression of the 'inhibitor of apoptosis' family of proteins. The protective effects of IL-33 may be limited by the neurohormonal factor endothelin-1, which increased expression of sST2 and inhibited IL-33 signaling through p38 MAP Kinase.

Atherosclerosis

21During atherosclerosis immune cells such as monocytes, T cells and mast cells infiltrate plaques within the intima of the arterial wall. The disease appears to be driven by a Th1 immune response with cytokines such as IL-12 and IFNγ inducing pathogenesis. Thus, it was hypothesized that IL-33 may have protective effects during atherosclerosis by inducing a Th1-to-Th2 switch of immune responses. In fact, treatment of ApoE-/- mice with IL-33 significantly reduced atherosclerotic lesion size in the aortic sinus and reduced plaque F4/80+ macrophage and CD3+ T cell content. IL-33 treatment increased levels of the Th2 cytokines IL-4, IL-5, and IL-13 but decreased levels of the Th1 cytokine IFNγ in serum and lymph node cells. Furthermore, IL-33-treated ApoE-/- mice also produced significantly elevated levels of protective anti-oxidized low-density lipoprotein (ox-LDL) IgM antibodies. Conversely, mice treated with intraperitoneal injections of sST2 developed significantly larger atherosclerotic plaques and enhanced IFNγ levels. Thus far, atherosclerosis development has not been studied in ApoE-/- or LDLR-/- mice also deficient in genes encoding either IL-33 or ST2 and these studies are required in order to examine the endogenous role of IL-33. Cell-based experiments have also shown that IL-33 has potent effects on macrophage-derived foam cell function in vitro providing further evidence for anti-atherosclerotic effects of IL-33. Taken together these results indicate that IL-33/ST2 signaling may play a protective role in atherosclerosis.

Obesity and type 2 diabetes

22Recently, expression of IL-33 and ST2 was reported in adipocytes and adipose tissues. Subsequently it was shown that treatment of adipocyte cultures in vitro with IL-33 induced the production of Th2 cytokines (IL-5 and IL-13), reduced lipid storage and decreased the expression of several genes associated with lipid metabolism and adipogenesis (e.g. C/EBPα, SREBP-1c, LXRα, LXRβ, and PPARγ). Furthermore, treatment of genetically obese diabetic (ob/ob) mice with IL-33 led to protective metabolic effects with reduced adiposity, reduced fasting glucose and improved glucose and insulin tolerance. Conversely, ST2-/- mice fed high fat diet for 6 months had increased body weight and fat mass, impaired insulin secretion and glucose regulation compared to wild-type controls. The protective effects of IL-33 on adipose tissue appear to be mediated via an increased production of Th2 cytokines and a switching of macrophage polarization from an M1 to an M2 phenotype (Figure 3). More recently, a newly identified population of cells expressing ST2 were found in adipose named natural helper cells or fat-associated lymphoid cluster (FALC) cells that produce large amounts of Th2 cytokines in response to IL-33, but the direct role of these cells in obesity is still unclear.

Conclusions

23IL-33 appears to be a crucial cytokine for Th2-mediated host defense and plays a central role in controlling immune responses in barrier tissues such as skin and intestine. It is able to activate cells of both the innate and adaptive immune system, and depending on the disease can either promote the resolution of inflammation or drive disease pathology. Manipulation of the IL-33/ST2 pathway therefore represents a promising new therapeutic strategy for treating or preventing various inflammatory disorders. However, many questions regarding the fundamental biology of IL-33 remain to be solved, including its nuclear effects and processing and release of IL-33 from cells. Furthermore, given the wide variety of cellular responses regulated by IL-33 and ST2, and in particular the cardio-protective effects of IL-33, this should be approached with caution.

List of abbreviations

24AMI: Acute myocardial infarction; CIA: Collagen-induced arthritis; CNS: Central nervous system; CV: Cardiovascular; HEV: High endothelial venules; HF: Heart failure; IL: Interleukin; IL:1RAcP- IL:1R accessory protein; MAPK: Mitogen-activated protein kinase; OA: Osteoarthritis; PsA: Psoriatic arthritis; RA: Rheumatoid arthritis; SIGIRR: Single Ig IL:1R-related molecule; SLE: Systemic lupus erythematosus; sST2: Soluble ST2; Th: T helper; TIR: Toll-interleukin-1 receptor; TLR: Toll-like receptor; UC: Ulcerative colitis

Competing interests

25The authors declare that they have no competing interests.

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Miller AM Xu D Asquith DL Denby L Li Y Sattar N Baker AH McInnes IB Liew FY IL-33 reduces the development of atherosclerosisJ Exp Med2008 205339346
Not in our library10.1084/jem.20071868
27.
Komai-Koma M Gilchrist DS McKenzie AN Goodyear CS Xu D Liew FY IL-33 activates B1 cells and exacerbates contact sensitivityJ Immunol2011 18625842591
Not in our library10.4049/jimmunol.1002103
28.
Cherry WB Yoon J Bartemes KR Iijima K Kita H A novel IL-1 family cytokine, IL-33, potently activates human eosinophilsJ Allergy Clin Immunol2008 12114841490
Not in our library10.1016/j.jaci.2008.04.005
29.
Allakhverdi Z Smith DE Comeau MR Delespesse G Cutting edge: The ST2 ligand IL-33 potently activates and drives maturation of human mast cellsJ Immunol2007 17920512054
Not in our library10.4049/jimmunol.179.4.2051
30.
Iikura M Suto H Kajiwara N Oboki K Ohno T Okayama Y Saito H Galli SJ Nakae S IL-33 can promote survival, adhesion and cytokine production in human mast cellsLab Invest2007 87971978
Not in our library10.1038/labinvest.3700663
31.
Smithgall MD Comeau MR Yoon BR Kaufman D Armitage R Smith DE IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cellsInt Immunol2008 2010191030
Not in our library10.1093/intimm/dxn060
32.
Schneider E Petit-Bertron AF Bricard R Levasseur M Ramadan A Girard JP Herbelin A Dy M IL-33 activates unprimed murine basophils directly in vitro and induces their in vivo expansion indirectly by promoting hematopoietic growth factor productionJ Immunol2009 18335913597
Not in our library10.4049/jimmunol.0900328
33.
Alves-Filho JC Sonego F Souto FO Freitas A Verri WA Jr Auxiliadora-Martins M Basile-Filho A McKenzie AN Xu D Cunha FQ Liew FY Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infectionNat Med2010 16708712
Not in our library10.1038/nm.2156
34.
Kurowska-Stolarska M Stolarski B Kewin P Murphy G Corrigan CJ Ying S Pitman N Mirchandani A Rana B van Rooijen N IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammationJ Immunol2009 18364696477
Not in our library10.4049/jimmunol.0901575
35.
Espinassous Q Garcia-de-Paco E Garcia-Verdugo I Synguelakis M von Aulock S Sallenave JM McKenzie AN Kanellopoulos J IL-33 enhances lipopolysaccharide-induced inflammatory cytokine production from mouse macrophages by regulating lipopolysaccharide receptor complexJ Immunol2009 18314461455
Not in our library10.4049/jimmunol.0803067
36.
Kropf P Bickle Q Herath S Klemenz R Muller I Organ-specific distribution of CD4+ T1/ST2+ Th2 cells in Leishmania major infectionEur J Immunol2002 3224502459
Not in our library10.1002/1521-4141(200209)32:9<2450::aid-immu2450>3.0.co;2-o
37.
Kropf P Herath S Klemenz R Muller I Signaling through the T1/ST2 molecule is not necessary for Th2 differentiation but is important for the regulation of type 1 responses in nonhealing Leishmania major infectionInfect Immun2003 7119611971
Not in our library10.1128/iai.71.4.1961-1971.2003
38.
Jones LA Roberts F Nickdel MB Brombacher F McKenzie AN Henriquez FL Alexander J Roberts CW IL-33 receptor (T1/ST2) signalling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondiiEur J Immunol2010 40426436
Not in our library10.1002/eji.200939705
39.
Humphreys NE Xu D Hepworth MR Liew FY Grencis RK IL-33, a potent inducer of adaptive immunity to intestinal nematodesJ Immunol2008 18024432449
Not in our library10.4049/jimmunol.180.4.2443
40.
Price AE Liang HE Sullivan BM Reinhardt RL Eisley CJ Erle DJ Locksley RM Systemically dispersed innate IL-13-expressing cells in type 2 immunityProc Natl Acad Sci USA2010 1071148911494
Not in our library10.1073/pnas.1003988107
41.
Neill DR Wong SH Bellosi A Flynn RJ Daly M Langford TK Bucks C Kane CM Fallon PG Pannell R Nuocytes represent a new innate effector leukocyte that mediates type-2 immunityNature2010 46413671370
Not in our library10.1038/nature08900
42.
Lloyd CM IL-33 family members and asthma - bridging innate and adaptive immune responsesCurr Opin Immunol2010 22800806
Not in our library10.1016/j.coi.2010.10.006
43.
Prefontaine D Lajoie-Kadoch S Foley S Audusseau S Olivenstein R Halayko AJ Lemiere C Martin JG Hamid Q Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cellsJ Immunol2009 18350945103
Not in our library10.4049/jimmunol.0802387
44.
Prefontaine D Nadigel J Chouiali F Audusseau S Semlali A Chakir J Martin JG Hamid Q Increased IL-33 expression by epithelial cells in bronchial asthmaJ Allergy Clin Immunol2010
Not in our library10.1016/j.jaci.2009.12.935
45.
Yagami A Orihara K Morita H Futamura K Hashimoto N Matsumoto K Saito H Matsuda A IL-33 Mediates Inflammatory Responses in Human Lung Tissue CellsJ Immunol2010
Not in our library10.4049/jimmunol.0903818
46.
Kondo Y Yoshimoto T Yasuda K Futatsugi-Yumikura S Morimoto M Hayashi N Hoshino T Fujimoto J Nakanishi K Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune systemInt Immunol2008 20791800
Not in our library10.1093/intimm/dxn037
47.
Stolarski B Kurowska-Stolarska M Kewin P Xu D Liew FY IL-33 exacerbates eosinophil-mediated airway inflammationJ Immunol2010 18534723480
Not in our library10.4049/jimmunol.1000730
48.
Zhiguang X Wei C Steven R Wei D Wei Z Rong M Zhanguo L Lianfeng Z Over-expression of IL-33 leads to spontaneous pulmonary inflammation in mIL-33 transgenic miceImmunol Lett2010 131159165
Not in our library10.1016/j.imlet.2010.04.005
49.
Liu X Li M Wu Y Zhou Y Zeng L Huang T Anti-IL-33 antibody treatment inhibits airway inflammation in a murine model of allergic asthmaBiochem Biophys Res Commun2009 386181185
Not in our library10.1016/j.bbrc.2009.06.008
50.
Coyle AJ Lloyd C Tian J Nguyen T Erikkson C Wang L Ottoson P Persson P Delaney T Lehar S Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responsesJ Exp Med1999 190895902
Not in our library10.1084/jem.190.7.895
51.
Hoshino K Kashiwamura S Kuribayashi K Kodama T Tsujimura T Nakanishi K Matsuyama T Takeda K Akira S The absence of interleukin 1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector functionJ Exp Med1999 19015411548
Not in our library10.1084/jem.190.10.1541
52.
Mangan NE Dasvarma A McKenzie AN Fallon PG T1/ST2 expression on Th2 cells negatively regulates allergic pulmonary inflammationEur J Immunol2007 3713021312
Not in our library10.1002/eji.200636520
53.
Louten J Rankin AL Li Y Murphy EE Beaumont M Moon C Bourne P McClanahan TK Pflanz S de Waal Malefyt R Endogenous IL-33 enhances Th2 cytokine production and T-cell responses during allergic airway inflammationInt Immunol2011
Not in our library10.1093/intimm/dxr006
54.
Talabot-Ayer D McKee T Gindre P Bas S Baeten DL Gabay C Palmer G Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritisJoint Bone Spine2011
Not in our library10.1016/j.jbspin.2011.02.011
55.
Xu D Jiang HR Kewin P Li Y Mu R Fraser AR Pitman N Kurowska-Stolarska M McKenzie AN McInnes IB Liew FY IL-33 exacerbates antigen-induced arthritis by activating mast cellsProc Natl Acad Sci USA2008 1051091310918
Not in our library10.1073/pnas.0801898105
56.
Palmer G Talabot-Ayer D Lamacchia C Toy D Seemayer CA Viatte S Finckh A Smith DE Gabay C Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritisArthritis Rheum2009 60738749
Not in our library10.1002/art.24305
57.
Mu R Huang HQ Li YH Li C Ye H Li ZG Elevated serum interleukin 33 is associated with autoantibody production in patients with rheumatoid arthritisJ Rheumatol2010 3720062013
Not in our library10.3899/jrheum.100184
58.
Matsuyama Y Okazaki H Tamemoto H Kimura H Kamata Y Nagatani K Nagashima T Hayakawa M Iwamoto M Yoshio T Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritisJ Rheumatol2010 371825
Not in our library10.3899/jrheum.090492
59.
Verri WA Jr Souto FO Vieira SM Almeida SC Fukada SY Xu D Alves-Filho JC Cunha TM Guerrero AT Mattos-Guimaraes RB IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapyAnn Rheum Dis2010 6916971703
Not in our library10.1136/ard.2009.122655
60.
Yang Z Liang Y Xi W Li C Zhong R Association of increased serum IL-33 levels with clinical and laboratory characteristics of systemic lupus erythematosus in Chinese populationClin Exp Med2010
Not in our library10.1007/s10238-010-0115-4
61.
Mok MY Huang FP Ip WK Lo Y Wong FY Chan EY Lam KF Xu D Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosusRheumatology (Oxford)2010 49520527
Not in our library10.1093/rheumatology/kep402
62.
Xu D Jiang HR Li Y Pushparaj PN Kurowska-Stolarska M Leung BP Mu R Tay HK McKenzie AN McInnes IB IL-33 Exacerbates Autoantibody-Induced ArthritisJ Immunol2010 18426202626
Not in our library10.4049/jimmunol.0902685
63.
Mun SH Ko NY Kim HS Kim JW Kim do K Kim AR Lee SH Kim YG Lee CK Lee SH Interleukin-33 stimulates formation of functional osteoclasts from human CD14(+) monocytesCell Mol Life Sci2010 6738833892
Not in our library10.1007/s00018-010-0410-y
64.
Schulze J Bickert T Beil FT Zaiss MM Albers J Wintges K Streichert T Klaetschke K Keller J Hissnauer TN Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cellsJ Bone Miner Res2010
Not in our library10.1002/jbmr.269
65.
Saleh H Eeles D Hodge JM Nicholson GC Gu R Pompolo S Gillespie MT Quinn JM Interleukin-33, a Target of Parathyroid Hormone and Oncostatin M, Increases Osteoblastic Matrix Mineral Deposition and Inhibits Osteoclast Formation in VitroEndocrinology2011
Not in our library10.1210/en.2010-1268
66.
Saidi S Bouri F Lencel P Duplomb L Baud'huin M Delplace S Leterme D Miellot F Heymann D Hardouin P IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodelingCytokine2011 53347354
Not in our library10.1016/j.cyto.2010.11.021
67.
Pushparaj PN Tay HK H'Ng SC Pitman N Xu D McKenzie A Liew FY Melendez AJ The cytokine interleukin-33 mediates anaphylactic shockProc Natl Acad Sci USA2009 10697739778
Not in our library10.1073/pnas.0901206106
68.
Theoharides TC Zhang B Kempuraj D Tagen M Vasiadi M Angelidou A Alysandratos KD Kalogeromitros D Asadi S Stavrianeas N IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skinProc Natl Acad Sci USA2010
Not in our library10.1073/pnas.1000803107
69.
Hueber AJ Alves-Filho JC Asquith DL Michels C Millar NL Reilly JH Graham GJ Miller AM McInnes IB IL-33 induces skin inflammation with mast cell and neutrophil activationEur J Immunol2011 in press
Not in our library10.1002/eji.201041360
70.
Yanaba K Yoshizaki A Asano Y Kadono T Sato S Serum IL-33 levels are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosisClin Rheumatol2011
Not in our library10.1007/s10067-011-1686-5
71.
Rankin AL Mumm JB Murphy E Turner S Yu N McClanahan TK Bourne PA Pierce RH Kastelein R Pflanz S IL-33 induces IL-13-dependent cutaneous fibrosisJ Immunol2010 18415261535
Not in our library10.4049/jimmunol.0903306
72.
Sponheim J Pollheimer J Olsen T Balogh J Hammarstrom C Loos T Kasprzycka M Sorensen DR Nilsen HR Kuchler AM Inflammatory bowel disease-associated interleukin-33 is preferentially expressed in ulceration-associated myofibroblastsAm J Pathol2010 17728042815
Not in our library10.2353/ajpath.2010.100378
73.
Verri WA Jr Guerrero AT Fukada SY Valerio DA Cunha TM Xu D Ferreira SH Liew FY Cunha FQ IL-33 mediates antigen-induced cutaneous and articular hypernociception in miceProc Natl Acad Sci USA2008 10527232728
Not in our library10.1073/pnas.0712116105
74.
Pastorelli L Garg RR Hoang SB Spina L Mattioli B Scarpa M Fiocchi C Vecchi M Pizarro TT Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritisProc Natl Acad Sci USA2010 10780178022
Not in our library10.1073/pnas.0912678107
75.
Beltran CJ Nunez LE Diaz-Jimenez D Farfan N Candia E Heine C Lopez F Gonzalez MJ Quera R Hermoso MA Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel diseaseInflamm Bowel Dis2009
Not in our library10.1002/ibd.21175
76.
Kobori A Yagi Y Imaeda H Ban H Bamba S Tsujikawa T Saito Y Fujiyama Y Andoh A Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitisJ Gastroenterol2010 459991007
Not in our library10.1007/s00535-010-0245-1
77.
Seidelin JB Bjerrum JT Coskun M Widjaya B Vainer B Nielsen OH IL-33 is upregulated in colonocytes of ulcerative colitisImmunol Lett2010 1288085
Not in our library10.1016/j.imlet.2009.11.001
78.
Ajdukovic J Tonkic A Salamunic I Hozo I Simunic M Bonacin D Interleukins IL-33 and IL-17/IL-17A in patients with ulcerative colitisHepatogastroenterology2010 5714421444
Not in our library
79.
Rani R Smulian AG Greaves DR Hogan SP Herbert DR TGF-beta limits IL-33 production and promotes the resolution of colitis through regulation of macrophage functionEur J Immunol2011
Not in our library10.1002/eji.201041135
80.
Hudson CA Christophi GP Gruber RC Wilmore JR Lawrence DA Massa PT Induction of IL-33 expression and activity in central nervous system gliaJ Leukoc Biol2008 84631643
Not in our library10.1189/jlb.1207830
81.
Yasuoka S Kawanokuchi J Parajuli B Jin S Doi Y Noda M Sonobe Y Takeuchi H Mizuno T Suzumura A Production and functions of IL-33 in the central nervous systemBrain Res2011 1385817
Not in our library10.1016/j.brainres.2011.02.045
82.
Chapuis J Hot D Hansmannel F Kerdraon O Ferreira S Hubans C Maurage CA Huot L Bensemain F Laumet G Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's diseaseMol Psychiatry2009 1410041016
Not in our library10.1038/mp.2009.10
83.
Yu JT Song JH Wang ND Wu ZC Zhang Q Zhang N Zhang W Xuan SY Tan L Implication of IL-33 gene polymorphism in Chinese patients with Alzheimer's diseaseNeurobiol Aging2010
Not in our library10.1016/j.neurobiolaging.2010.07.003
84.
Yoshida K Arai T Yokota T Komatsu N Miura Y Yanagisawa K Tetsuka T Tominaga S Studies on natural ST2 gene products in the human leukemic cell line UT-7 using monoclonal antihuman ST2 antibodiesHybridoma1995 14419427
Not in our library10.1089/hyb.1995.14.419
85.
Tsuchiya T Ohshima K Karube K Yamaguchi T Suefuji H Hamasaki M Kawasaki C Suzumiya J Tomonaga M Kikuchi M Th1, Th2, and activated T-cell marker and clinical prognosis in peripheral T-cell lymphoma, unspecified: comparison with AILD, ALCL, lymphoblastic lymphoma, and ATLLBlood2004 103236241
Not in our library10.1182/blood-2002-05-1352
86.
Jovanovic I Radosavljevic G Mitrovic M Lisnic Juranic V McKenzie A Arsenijevic N Jonjic S Lukic M ST2 Deletion Enhances Innate and Acquired Immunity to Murine Mammary CarcinomaEur J Immunol2011
Not in our library10.1002/eji.201141417
87.
Choi YS Choi HJ Min JK Pyun BJ Maeng YS Park H Kim J Kim YM Kwon YG Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide productionBlood2009 11431173126
Not in our library10.1182/blood-2009-02-203372
88.
Kuchler AM Pollheimer J Balogh J Sponheim J Manley L Sorensen DR De Angelis PM Scott H Haraldsen G Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activationAm J Pathol2008 17312291242
Not in our library10.2353/ajpath.2008.080014
89.
Bartunek J Delrue L Van Durme F Muller O Casselman F De Wiest B Croes R Verstreken S Goethals M de Raedt H Nonmyocardial production of ST2 protein in human hypertrophy and failure is related to diastolic loadJ Am Coll Cardiol2008 5221662174
Not in our library10.1016/j.jacc.2008.09.027
90.
The IL-1-Like Cytokine IL-33 Is Constitutively Expressed in the Nucleus of Endothelial Cells and Epithelial Cells In Vivo: A Novel ‘Alarmin’? · 2008
No notice
91.
Wood IS Wang B Trayhurn P IL-33, a recently identified interleukin-1 gene family member, is expressed in human adipocytesBiochem Biophys Res Commun2009 384105109
Not in our library10.1016/j.bbrc.2009.04.081
92.
Sanada S Hakuno D Higgins LJ Schreiter ER McKenzie AN Lee RT IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling systemJ Clin Invest2007 11715381549
Not in our library10.1172/jci30634
93.
Weinberg EO Shimpo M De Keulenaer GW MacGillivray C Tominaga S Solomon SD Rouleau JL Lee RT Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarctionCirculation2002 10629612966
Not in our library10.1161/01.cir.0000038705.69871.d9
94.
Kuhn E Addona T Keshishian H Burgess M Mani DR Lee RT Sabatine MS Gerszten RE Carr SA Developing multiplexed assays for troponin I and interleukin-33 in plasma by peptide immunoaffinity enrichment and targeted mass spectrometryClin Chem2009 5511081117
Not in our library10.1373/clinchem.2009.123935
95.
Seki K Sanada S Kudinova AY Steinhauser ML Handa V Gannon J Lee RT Interleukin-33 prevents apoptosis and improves survival after experimental myocardial infarction through ST2 signalingCirc Heart Fail2009 2684691
Not in our library10.1161/circheartfailure.109.873240
96.
Yndestad A Marshall AK Hodgkinson JD Thamel L Sugden PH Clerk A Modulation of interleukin signalling and gene expression in cardiac myocytes by endothelin-1Int J Biochem Cell Biol2010 42263272
Not in our library10.1016/j.biocel.2009.10.021
97.
Hansson GK Hermansson A The immune system in atherosclerosisNat Immunol2011 12204212
Not in our library10.1038/ni.2001
98.
Davenport P Tipping PG The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient miceAm J Pathol2003 16311171125
Not in our library10.1016/s0002-9440(10)63471-2
99.
Gupta S Pablo AM Jiang X Wang N Tall AR Schindler C IFN-gamma potentiates atherosclerosis in ApoE knock-out miceJ Clin Invest1997 9927522761
Not in our library10.1172/jci119465
100.
McLaren JE Michael DR Salter RC Ashlin TG Calder CJ Miller AM Liew FY Ramji DP IL-33 reduces macrophage foam cell formationJ Immunol2010 18512221229
Not in our library10.4049/jimmunol.1000520
101.
Miller AM Asquith DL Hueber AJ Anderson LA Holmes WM McKenzie AN Xu D Sattar N McInnes IB Liew FY Interleukin-33 induces protective effects in adipose tissue inflammation during obesity in miceCirc Res2010 107650658
Not in our library10.1161/circresaha.110.218867
102.
Moro K Yamada T Tanabe M Takeuchi T Ikawa T Kawamoto H Furusawa J Ohtani M Fujii H Koyasu S Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cellsNature2010 463540544
Not in our library10.1038/nature08636
103.
Shimpo M Morrow DA Weinberg EO Sabatine MS Murphy SA Antman EM Lee RT Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarctionCirculation2004 10921862190
Not in our library10.1161/01.cir.0000127958.21003.5a
104.
Sabatine MS Morrow DA Higgins LJ MacGillivray C Guo W Bode C Rifai N Cannon CP Gerszten RE Lee RT Complementary roles for biomarkers of biomechanical strain ST2 and N-terminal prohormone B-type natriuretic peptide in patients with ST-elevation myocardial infarctionCirculation2008 11719361944
Not in our library10.1161/circulationaha.107.728022
105.
Weir RA Miller AM Murphy GE Clements S Steedman T Connell JM McInnes IB Dargie HJ McMurray JJ Serum soluble ST2: a potential novel mediator in left ventricular and infarct remodeling after acute myocardial infarctionJ Am Coll Cardiol2010 55243250
Not in our library10.1016/j.jacc.2009.08.047
106.
Brown AM Wu AH Clopton P Robey JL Hollander JE ST2 in emergency department chest pain patients with potential acute coronary syndromesAnn Emerg Med2007 50153158158 e151.
Not in our library10.1016/j.annemergmed.2007.02.015
107.
Weinberg EO Shimpo M Hurwitz S Tominaga S Rouleau JL Lee RT Identification of serum soluble ST2 receptor as a novel heart failure biomarkerCirculation2003 107721726
Not in our library10.1161/01.cir.0000047274.66749.fe
108.
Mueller T Dieplinger B Gegenhuber A Poelz W Pacher R Haltmayer M Increased plasma concentrations of soluble ST2 are predictive for 1-year mortality in patients with acute destabilized heart failureClin Chem2008 54752756
Not in our library10.1373/clinchem.2007.096560
109.
Rehman SU Mueller T Januzzi JL Jr Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failureJ Am Coll Cardiol2008 5214581465
Not in our library10.1016/j.jacc.2008.07.042
110.
Boisot S Beede J Isakson S Chiu A Clopton P Januzzi J Maisel AS Fitzgerald RL Serial sampling of ST2 predicts 90-day mortality following destabilized heart failureJ Card Fail2008 14732738
Not in our library10.1016/j.cardfail.2008.06.415
111.
Pascual-Figal DA Ordonez-Llanos J Tornel PL Vazquez R Puig T Valdes M Cinca J de Luna AB Bayes-Genis A Soluble ST2 for predicting sudden cardiac death in patients with chronic heart failure and left ventricular systolic dysfunctionJ Am Coll Cardiol2009 5421742179
Not in our library10.1016/j.jacc.2009.07.041
112.
Porcel JM Martinez-Alonso M Cao G Bielsa S Sopena A Esquerda A Biomarkers of heart failure in pleural fluidChest2009 136671677
Not in our library10.1378/chest.09-0270
113.
Bayes-Genis A Pascual-Figal D Januzzi JL Maisel A Casas T Valdes Chavarri M Ordonez-Llanos J Soluble ST2 Monitoring Provides Additional Risk Stratification for Outpatients With Decompensated Heart FailureRev Esp Cardiol2010 6311711178
Not in our library10.1016/s1885-5857(10)70231-0
114.
Manzano-Fernandez S Mueller T Pascual-Figal D Truong QA Januzzi JL Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fractionAm J Cardiol2011 107259267
Not in our library10.1016/j.amjcard.2010.09.011
115.
Ky B French B McCloskey K Rame JE McIntosh E Shahi P Dries DL Tang WH Wu AH Fang JC High-Sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart FailureCirc Heart Fail2011 4180187
Not in our library10.1161/circheartfailure.110.958223
116.
Szerafin T Brunner M Horvath A Szentgyorgyi L Moser B Boltz-Nitulescu G Peterffy A Hoetzenecker K Steinlechner B Wolner E Ankersmit HJ Soluble ST2 protein in cardiac surgery: a possible negative feedback loop to prevent uncontrolled inflammatory reactionsClin Lab2005 51657663
Not in our library
117.
Szerafin T Niederpold T Mangold A Hoetzenecker K Hacker S Roth G Lichtenauer M Dworschak M Wolner E Ankersmit HJ Secretion of soluble ST2 - possible explanation for systemic immunosuppression after heart surgeryThorac Cardiovasc Surg2009 572529
Not in our library10.1055/s-2008-1039044
118.
Daniels LB Clopton P Iqbal N Tran K Maisel AS Association of ST2 levels with cardiac structure and function and mortality in outpatientsAm Heart J2010 160721728
Not in our library10.1016/j.ahj.2010.06.033
119.
Januzzi JL Jr Peacock WF Maisel AS Chae CU Jesse RL Baggish AL O'Donoghue M Sakhuja R Chen AA van Kimmenade RR Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) studyJ Am Coll Cardiol2007 50607613
Not in our library10.1016/j.jacc.2007.05.014
120.
Dieplinger B Gegenhuber A Kaar G Poelz W Haltmayer M Mueller T Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency departmentClin Biochem2010 43714719
Not in our library10.1016/j.clinbiochem.2010.02.002
121.
Martinez-Rumayor A Camargo CA Green SM Baggish AL O'Donoghue M Januzzi JL Soluble ST2 plasma concentrations predict 1-year mortality in acutely dyspneic emergency department patients with pulmonary diseaseAm J Clin Pathol2008 130578584
Not in our library10.1309/wmg2bfrc97mkkqkp
122.
Rehman SU Martinez-Rumayor A Mueller T Januzzi JL Jr Independent and incremental prognostic value of multimarker testing in acute dyspnea: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) studyClin Chim Acta2008 3924145
Not in our library10.1016/j.cca.2008.03.002
123.
Shah RV Chen-Tournoux AA Picard MH van Kimmenade RR Januzzi JL Serum levels of the interleukin-1 receptor family member ST2, cardiac structure and function, and long-term mortality in patients with acute dyspneaCirc Heart Fail2009 2311319
Not in our library10.1161/circheartfailure.108.833707

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