KU812 cells provide a novel in vitro model of the human IL-33/ST2L axis: Functional responses and identification of signaling pathways

Tare, Nadine S.; Liu, Hongli; Morschauser, A; Cote-Sierra, Javier; Ju, G; Renzetti, Louis M.; Lin, Tai-An

doi:10.1016/j.yexcr.2010.04.007

Cited by 20 publications

(13 citation statements)

References 48 publications

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“…The activation of NF-kB by IL-33 stimulation has previously been reported in myocytes, mast cells and basophils [33, 54, 91]. IL-33 binding to ST2L triggers the accumulation of adaptor proteins such as myeloid differentiation primary response gene 88 (MyD88) and TNF receptor associated factor 6 (TRAF6).…”

Section: Discussionmentioning

confidence: 98%

“…Published research had demonstrated that NF-kB activation was upstream of IL-33 induced IL-6 and MCP-1 production in mouse embryonic fibroblasts expressing ST2L [92]. In addition, NF-kB activation was also demonstrated to be necessary for IL-33 induced IL-13 production in a human chronic myelogenous leukemia cell line (KU812) [91]. Interestingly our data illustrating that the activation of NF-kB pathway is not necessary for IL-33 induced MCP-1 expression suggests that different pathways are required for specific downstream effects of IL-33.…”

Section: Discussionmentioning

confidence: 99%

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Effects of interleukin-33 on cardiac fibroblast gene expression and activity

Zhu

Carver

2012

Cytokine

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Interleukin-33 (IL-33) is a recently described member of the interleukin-1 (IL-1) family. It is produced by diverse cell types in response to a variety of stresses including hemorrhage and increased mechanical load. Though only relatively recently discovered, IL-33 has been shown to participate in several pathological processes including promoting type 2 T helper cell-associated autoimmune diseases. In contrast, IL-33 has been also found to have protective effects in cardiovascular diseases. Recent studies have illustrated that IL-33 attenuates cardiac fibrosis induced by increased cardiovascular load in mice (transaortic constriction). Since cardiac fibrosis is largely dependent on increased production of extracellular matrix by cardiac fibroblasts, we hypothesized that IL-33 directly inhibits pro-fibrotic activities of these cells. Experiments have been carried out with isolated rat cardiac fibroblasts to evaluate the effects of IL-33 on the modulation of cardiac fibroblast gene expression and function to test this hypothesis. The expression of the IL-33 receptor, interleukin-1 receptor-like 1 (ST2), was detected at the mRNA and protein levels in isolated adult rat cardiac fibroblasts. Subsequently, the effects of IL-33 treatment (0–100 ng/ml) on the expression of extracellular matrix proteins and pro-inflammatory cytokines/chemokines were examined as well as the effects on rat cardiac fibroblast activities including proliferation, collagen gel contraction and migration. While IL-33 did not directly inhibit collagen I and collagen III production, it yielded a dose-dependent increase in the expression of interleukin-6 and monocyte chemotactic protein-1. Treatment of rat cardiac fibroblasts with IL-33 also impaired the migratory activity of these cells. Further experiments illustrated that IL-33 rapidly activated multiple signaling pathways including extracellular signal-regulated kinases, p38 mitogen-activated protein kinase, c-Jun N-terminal kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in a dose-dependent manner. Experiments were carried out with pharmacological inhibitors to determine the role of specific signaling pathways in the response of fibroblasts to IL-33. These experiments illustrated that the activation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinases are critical to the increased production of interleukin-6 and monocyte chemotactic protein-1 in response to IL-33. These studies suggest that IL-33 has an important role in the modulation of fibroblast function and gene expression. Surprisingly, IL-33 had no effect on the expression of genes encoding extracellular matrix components or on proliferation, markers typical of fibrosis. The major effects of IL-33 detected in these studies included inhibition of cell migration and activation of cytokine/chemokine expression. The previously reported inhibition of cardiac fibrosis may include more complicated mechanisms that involve other cardiac cell types. Future studies aimed at determin...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Effects of interleukin-33 on cardiac fibroblast gene expression and activity

Zhu

Carver

2012

Cytokine

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“…All other intracellular variants were associated with increased sST2 expression, indicating that signal transduction via the ST2L intracellular domain plays an important role in regulating sST2. This occurs via alterations in ST2 signaling pathways, including transcription factors NF-κB and AP-1 (28,29), which are known to regulate sST2 expression, and the PI3K/AKT/mTOR pathway, which is known to regulate ST2L expression (30). The A433T and Q501R variants specifically demonstrated enhanced sST2 expression after IL-33 induction, which was blocked by both anti-ST2L mAb and anti-IL-1β.…”

Section: Discussionmentioning

confidence: 99%

Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling

Ho¹,

Chen²,

Chen³

et al. 2013

J. Clin. Invest.

106

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The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.

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“…In vitro-translated full-length IL-33 or mature forms (5 μL of lysate/well; 24-h treatment) were used to stimulate IL-33-responsive MC/9 mast cells (ATCC; 10 5 to 2 × 10 5 cells/well in 96-well plates) (23) and KU812 basophil-like chronic myelogenous leukemia cells (ATCC; 5 × 10 5 cells/well in 96-well plates) (38). Cytokine levels in supernatants were determined using DuoSet IL-6 and IL-5 ELISAs (R&D Systems).…”

Section: Methodsmentioning

confidence: 99%

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

Lefrançais

Roga

Gautier

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

506

464

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Interleukin-33 (IL-33) (NF-HEV) is a chromatin-associated nuclear cytokine from the IL-1 family, which has been linked to important diseases, including asthma, rheumatoid arthritis, ulcerative colitis, and cardiovascular diseases. IL-33 signals through the ST2 receptor and drives cytokine production in type 2 innate lymphoid cells (ILCs) (natural helper cells, nuocytes), T-helper (Th)2 lymphocytes, mast cells, basophils, eosinophils, invariant natural killer T (iNKT), and natural killer (NK) cells. We and others recently reported that, unlike IL-1β and IL-18, full-length IL-33 is biologically active independently of caspase-1 cleavage and that processing by caspases results in IL-33 inactivation. We suggested that IL-33, which is released upon cellular damage, may function as an endogenous danger signal or alarmin, similar to IL-1α or high-mobility group box 1 protein (HMGB1). Here, we investigated the possibility that IL-33 activity may be regulated by proteases released during inflammation. Using a combination of in vitro and in vivo approaches, we demonstrate that neutrophil serine proteases cathepsin G and elastase can cleave full-length human IL-33 1-270 and generate mature forms IL-33 , and IL-33 . These forms are produced by activated human neutrophils ex vivo, are biologically active in vivo, and have a ∼10-fold higher activity than full-length IL-33 in cellular assays. Murine IL-33 is also cleaved by neutrophil cathepsin G and elastase, and both fulllength and cleaved endogenous IL-33 could be detected in the bronchoalveolar lavage fluid in an in vivo model of acute lung injury associated with neutrophil infiltration. We propose that the inflammatory microenvironment may exacerbate disease-associated functions of IL-33 through the generation of highly active mature forms.innate immunity | inflammatory protease | serine protease inhibitor | alveolar epithelium C ytokines of the IL-1 family (IL-1α, IL-1β, IL-18) play a major role in inflammatory, infectious, and autoimmune diseases (1-3). IL-33 [previously known as nuclear factor from high endothelial venule or NF-HEV (4, 5)], is a chromatin-associated nuclear cytokine from the IL-1 family (6, 7), which has been linked to important diseases (8-10), including asthma (11), rheumatoid arthritis (12, 13), ulcerative colitis (14), and cardiovascular diseases (15).IL-33 signals through the ST2 receptor (4), a member of the IL-1 receptor family, which is expressed (or induced) on various immune cell types, including mast cells, basophils, eosinophils, Thelper (Th)2 lymphocytes, invariant natural killer T (iNKT) and natural killer (NK) cells, macrophages, dendritic cells, and neutrophils (8-10). IL-33 stimulation of ST2 on Th2 cells induces secretion of the Th2 cytokines IL-5 and IL-13 (4, 16). Recently, IL-33 has been shown to drive production of extremely high amounts of these Th2 cytokines by type 2 innate lymphoid cells (ILCs) (natural helper cells, nuocytes, innate helper 2 cells), which play important roles in innate immune responses, after helminth infec...

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KU812 cells provide a novel in vitro model of the human IL-33/ST2L axis: Functional responses and identification of signaling pathways

Cited by 20 publications

References 48 publications

Effects of interleukin-33 on cardiac fibroblast gene expression and activity

Effects of interleukin-33 on cardiac fibroblast gene expression and activity

Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling

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

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