Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis

Pastorelli, Luca; Garg, Rekha; Hoang, Sharon B.; Spina, Luisa; Mattioli, Benedetta; Scarpa, Melania; Fiocchi, Claudio; Vecchi, Maurizio; Pizarro, Theresa T.

doi:10.1073/pnas.0912678107

Cited by 362 publications

(426 citation statements)

References 41 publications

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“…Interestingly, IgG-ICs have been shown to contribute to the pathogenesis of rheumatoid arthritis and inflammatory bowel disease, which are both associated with elevated levels of IL-33 in the sera and tissues (64)(65)(66)(67)(68). While our findings contribute to the understanding of how IL-33 affects Th2-mediated diseases, it is not clear how IL-33 may function in these Th17-mediated diseases.…”

Section: Discussionmentioning

confidence: 79%

IL-33–dependent induction of allergic lung inflammation by FcγRIII signaling

Tjota¹,

Williams²,

Lu³

et al. 2013

J. Clin. Invest.

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Atopic asthma is a chronic inflammatory disease of the lungs generally marked by excessive Th2 inflammation. The role of allergen-specific IgG in asthma is still controversial; however, a receptor of IgG-immune complexes (IgG-ICs), FcγRIII, has been shown to promote Th2 responses through an unknown mechanism. Herein, we demonstrate that allergen-specific IgG-ICs, formed upon reexposure to allergen, promoted Th2 responses in two different models of IC-mediated inflammation that were independent of a preformed T cell memory response. Development of Th2-type airway inflammation was shown to be both FcγRIII and TLR4 dependent, and T cells were necessary and sufficient for this process to occur, even in the absence of type 2 innate lymphoid cells. We sought to identify downstream targets of FcγRIII signaling that could contribute to this process and demonstrated that bone marrow-derived DCs, alveolar macrophages, and respiratory DCs significantly upregulated IL-33 when activated through FcγRIII and TLR4. Importantly, IC-induced Th2 inflammation was dependent on the ST2/IL-33 pathway. Our results suggest that allergen-specific IgG can enhance secondary responses by ligating FcγRIII on antigen-presenting cells to augment development of Th2-mediated responses in the lungs via an IL-33-dependent mechanism.

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Section: Discussionmentioning

confidence: 79%

IL-33–dependent induction of allergic lung inflammation by FcγRIII signaling

Tjota¹,

Williams²,

Lu³

et al. 2013

J. Clin. Invest.

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“…The involvement of sST2 has been observed in a variety of pathological conditions characterized by: (1) intravascular inflammation [145,[148][149][150][151] (i.e. myocardial infarction [152][153][154], atherosclerotic vascular disease [155], sepsis and trauma [149,150]); and (2) an imbalance of Th1/Th2 immune response [141,156,157] (i.e. asthma and other allergic conditions [145,148,158,159]), both of which are also observed in patients with preeclampsia [23,25,132,160,161].…”

Section: Introductionmentioning

confidence: 99%

Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic factors in preeclampsia

Stampalija

Chaiworapongsa

Romero

et al. 2013

The Journal of Maternal-Fetal & Neonatal Medicine

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Objectives: Angiogenic/anti-angiogenic factors have emerged as one of the promising biomarkers for the prediction of preeclampsia. Since not all patients with preeclampsia can be identified by these analytes, the search for additional biomarkers continues. The soluble form of ST2 (sST2), a protein capable of binding to interleukin (IL)-33 and thus contributing to a Th1-biased immune response, has been reported to be elevated in maternal plasma of women with preeclampsia. The aims of this study were to examine: (1) differences in maternal plasma concentrations of sST2 and IL-33 between women diagnosed with preeclampsia and those having uncomplicated pregnancies; (2) the relationship between sST2, umbilical and uterine artery Doppler velocimetry, and the severity of preeclampsia; and (3) the performance of sST2 and angiogenic/anti-angiogenic factors in identifying patients with preeclampsia at the time of diagnosis. Methods: This cross-sectional study included women with preeclampsia (n ¼ 106) and women with an uncomplicated pregnancy (n ¼ 131). Plasma concentrations of sST2, IL-33, soluble vascular endothelial growth factor receptor (sVEGFR)-1, soluble endoglin (sEng) and placental growth factor (PlGF) were determined by enzyme linked immune sorbent assay. Area under the receiver operating characteristic curve (AUC) for the identification of preeclampsia was examined for each analyte. Results: (1) Patients with preeclampsia had a higher mean plasma concentrations of sST2 than those with an uncomplicated pregnancy (p50.0001), while no significant difference in the mean plasma concentration of IL-33 between the two groups was observed; (2) the magnitude of this difference was greater in early-onset, compared to late-onset disease, and in severe compared to mild preeclampsia; (3) sST2 plasma concentrations did not correlate with the results of uterine or umbilical artery Doppler velocimetry (p ¼ 0.7 and p ¼ 1, respectively) among women with preeclampsia; (4) sST2 correlated positively with plasma concentrations of sVEGFR1-1 and sEng (Spearman's Rho ¼ 0.72 and 0.63; each p50.0001), and negatively with PlGF (Spearman's Rho ¼ À0.56, p50.0001); and (5) while the AUC achieved by sST2 and angiogenic/anti-angiogenic factors in identifying women with preeclampsia at the time of diagnosis were non-significantly different prior to term (537 weeks of gestation), thereafter the AUC achieved by sST2 was significantly less than that achieved by angiogenic/anti-angiogenic factors. Conclusions: Preeclampsia is associated with increased maternal plasma concentrations of sST2. The findings that sST2 concentrations do not correlate with uterine or umbilical artery Doppler velocimetry in women with preeclampsia suggest that elevated maternal plasma sST2 concentrations in preeclampsia are not related to the increased impedance to flow in the uteroplacental circulation. The performance of sST2 in identifying preeclampsia at the time of diagnosis prior to 37 weeks of gestation was comparable to that of angiogenic/anti-angiogenic f...

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“…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)(9)(10), including asthma (11), rheumatoid arthritis (12,13), ulcerative colitis (14), and cardiovascular diseases (15).…”

mentioning

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.

500

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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Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis

Cited by 362 publications

References 41 publications

IL-33–dependent induction of allergic lung inflammation by FcγRIII signaling

IL-33–dependent induction of allergic lung inflammation by FcγRIII signaling

Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic factors in preeclampsia

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

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