IL-33 is produced by colon fibroblasts and differentially regulated in acute and chronic murine colitis.
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ABSTRACT:
SUBMITTER: Waddell A
PROVIDER: S-EPMC8100152 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IL-33, a member of the IL-1 cytokine family that signals through ST2, is upregulated in ulcerative colitis (UC); however, the role of IL-33 in colitis remains unclear. IL-33 augments type 2 immune responses, which have been implicated in UC pathogenesis. We sought to determine the role of IL-33 signaling in oxazolone (OXA) colitis, a type 2 cytokine-mediated murine model of UC.Colon mucosal IL-33 expression was compared between pediatric and adult UC and non-IBD patients using immunohistochemistry and real-time PCR. OXA colitis was induced in WT, IL-33, and ST2 mice, and histopathology, cytokine levels, and goblet cells were assessed. Transepithelial resistance was measured across IL-33-treated T84 cell monolayers.Colon mucosal IL-33 was increased in pediatric patients with active UC and in OXA colitis. IL-33 and ST2 OXA mice exhibited increased disease severity compared with WT OXA mice. OXA induced a mixed mucosal cytokine response, but few differences were observed between OXA WT and IL-33 or ST2 mice. Goblet cells were significantly decreased in IL-33 and ST2 OXA compared with WT OXA mice. IL-33 augmented transepithelial resistance in T84 cells, and this effect was blocked by the ERK1/2 inhibitor PD98,059.OXA colitis is exacerbated in IL-33 and ST2 mice. Increased mucosal IL-33 in human UC and murine colitis may be a homeostatic response to limit inflammation, potentially through effects on epithelial barrier function. Further investigation of IL-33 protective mechanisms would inform the development of novel therapeutic approaches.
| S-EPMC4654638 | biostudies-literature
Project description:Entamoeba histolytica is a pathogenic protozoan parasite that causes intestinal colitis, diarrhea, and in some cases, liver abscess. Through transcriptomics analysis, we observed that E. histolytica infection was associated with increased expression of IL-33 mRNA in both the human and murine colon. IL-33, the IL-1 family cytokine, is released after cell injury to alert the immune system of tissue damage. Treatment with recombinant IL-33 protected mice from amebic infection and intestinal tissue damage; moreover, blocking IL-33 signaling made mice more susceptible to amebiasis. IL-33 limited the recruitment of inflammatory immune cells and decreased the pro-inflammatory cytokine IL-6 in the cecum. Type 2 immune responses were upregulated by IL-33 treatment during amebic infection. Interestingly, administration of IL-33 protected RAG2-/- mice but not RAG2-/-γc-/- mice, demonstrating that IL-33-mediated protection required the presence of innate lymphoid cells (ILCs). IL-33 induced recruitment of ILC2 but not ILC1 and ILC3 in RAG2-/- mice. At baseline and after amebic infection, there was a significantly higher IL13+ILC2s in C57BL/J mice, which are naturally resistant to amebiasis, than CBA/J mice. Adoptive transfer of ILC2s to RAG2-/-γc-/- mice restored IL-33-mediated protection. These data reveal that the IL-33-ILC2 pathway is an important host defense mechanism against amebic colitis.
| S-EPMC8732277 | biostudies-literature
Project description:Eosinophils are major effector cells in type 2 inflammatory responses and become activated in response to IL-4 and IL-33, yet the molecular mechanisms and cooperative interaction between these cytokines remain unclear. Our objective was to investigate the molecular mechanism and cooperation of IL-4 and IL-33 in eosinophil activation. Eosinophils derived from bone marrow or isolated from Il5-transgenic mice were activated in the presence of IL-4 or IL-33 for 1 or 4 h, and the transcriptome was analyzed by RNA sequencing. The candidate genes were validated by quantitative PCR and ELISA. We demonstrated that murine-cultured eosinophils respond to IL-4 and IL-33 by phosphorylation of STAT-6 and NF-κB, respectively. RNA sequence analysis of murine-cultured eosinophils indicated that IL-33 induced 519 genes, whereas IL-4 induced only 28 genes, including 19 IL-33-regulated genes. Interestingly, IL-33 induced eosinophil activation via two distinct mechanisms, IL-4 independent and IL-4 secretion/autostimulation dependent. Anti-IL-4 or anti-IL-4Rα Ab-treated cultured and mature eosinophils, as well as Il4- or Stat6-deficient cultured eosinophils, had attenuated protein secretion of a subset of IL-33-induced genes, including Retnla and Ccl17. Additionally, IL-33 induced the rapid release of preformed IL-4 protein from eosinophils by a NF-κB-dependent mechanism. However, the induction of most IL-33-regulated transcripts (e.g., Il6 and Il13) was IL-4 independent and blocked by NF-κB inhibition. In conclusion, we have identified a novel activation pathway in murine eosinophils that is induced by IL-33 and differentially dependent upon an IL-4 auto-amplification loop.
| S-EPMC3807853 | biostudies-literature
Project description:OBJECTIVE:We tested the hypothesis that the expression of IL-33 in MS is dynamic and is likely to reflect the clinical and radiological changes during the course of RRMS. METHODS:MS with either clinical or radiological relapses were recruited for the study and followed for one year. IL-33 and a panel of genes was measured by q PCR and flow cytometry at different time points. RESULTS:Among 22 RRMS patients, 4 patients showed highest levels of IL-33 at the time they were recruited to the study (Month 0); in 14 patients highest levels of IL-33 were seen between 6-11 months after relapse and in 4 patients maximal levels of IL-33 were seen 12 months after relapse. A similar pattern of IL-33 kinetics was seen when IL-33 was measured by flow cytometry in an additional cohort of 12 patients. The timing of the improvement clinically did not correlate with IL-33 expression with highest expression levels either preceding or following clinical recovery. From our whole genome RNA-sequencing data we found a strong correlation between expression levels of IL-33 and a ~2000 mRNA genes. However, none of these genes encoded proteins involved in either innate or adaptive immunity. Rather, many of the genes that correlated highly with IL-33 encoded to proteins involved in DNA repair or mitochondrial function and mRNA splicing pathways. INTERPRETATION:Given the neuro-reparative and remodeling functions attributed to IL-33, it is likely that some of the novel genes we have uncovered may be involved in repair and recovery of the CNS in MS.
| S-EPMC6298727 | biostudies-literature
Project description:IL-38 is a recently discovered cytokine and member of the IL-1 Family. In the IL-1 Family, IL-38 is unique because the cytokine is primarily a B lymphocyte product and functions to suppress inflammation. Studies in humans with inflammatory bowel disease (IBD) suggest that IL-38 may be protective for ulcerative colitis or Crohn's disease, and that IL-38 acts to maintain homeostasis in the intestinal tract. Here we investigated the role of endogenous IL-38 in experimental colitis in mice deficient in IL-38 by deletion of exons 1-4 in C57 BL/6 mice. Compared to WT mice, IL-38 deficient mice subjected to dextran sulfate sodium (DSS) showed greater severity of disease, more weight loss, increased intestinal permeability, and a worse histological phenotype including increased neutrophil influx in the colon. Mice lacking IL-38 exhibited elevated colonic Nlrp3 mRNA and protein levels, increased caspase-1 activation, and the concomitant increased processing of IL-1β precursor into active IL-1β. Expression of IL-1α, an exacerbator of IBD, was also upregulated. Colonic myleloperoxidase protein and Il17a, and Il17f mRNA levels were higher in the IL-38 deficient mice. Daily treatment of IL-38 deficient mice with an NLRP3 inhibitor attenuated diarrhea and weight loss during the recovery phase. These data implicate endogenous IL-38 as an anti-inflammatory cytokine that reduces DSS colitis severity. We propose that a relative deficiency of IL-38 contributes to IBD by disinhibition of the NLRP3 inflammasome.
| S-EPMC9181991 | biostudies-literature
Project description:PURPOSE:Inflammatory bowel disease (IBD) primarily includes ulcerative colitis (UC) and Crohn's disease (CD). Thymic stromal lymphopoietin (TSLP) is a cytokine produced by intestinal epithelial cells (IECs) with immunomodulatory properties that plays an important role in the development of regulatory T cell (Treg) responses and tolerance in the gut. On the other hand, IL-33 has been considered as a cytokine with two different properties, inflammatory and anti-inflammatory functions, the latter may play a protective role against chronic intestinal inflammation. In the present study, we investigated the relative gene expression levels of TSLP and IL-33 molecules in ulcerative colitis. METHODS:Patients with clinical symptoms of colitis undergoing a routine diagnostic colonoscopy were included in this study. Biopsy specimens were collected and divided into two parts. One part was fixed and processed for routine histopathological examinations and the other part was stored for RNA extraction. TSLP and IL-33 gene expression were determined using the SYBR Green qRT-PCR. RESULTS:The expression level of TSLP and IL-33 were significantly lower in UC patients compared with the control group. Moreover, the expressions of these cytokines were more down-regulated in severe UC patients compared with mild and moderate ones and the control group. We also showed a positive correlation between low expression of TSLP and IL-33 and the severity of UC disease. CONCLUSIONS:In this study, we showed decreased mRNA expression levels of TSLP and IL-33 in UC patients and also a negative correlation between expression of TSLP and IL-33 and severity of UC disease.
| S-EPMC6416230 | biostudies-literature
Project description:Inflammatory bowel diseases (IBD) affect over 5 million individuals in the industrialized world, with an increasing incidence rate worldwide. IBD also predisposes affected individuals to development of colorectal cancer, which is a leading cause of cancer-related deaths in adults. Mutations in genes encoding molecules in the IL-33 signaling pathway are associated with colitis and colitis-associated cancer (CAC), but how IL-33 modulates gut homeostasis is unclear. Here, we have shown that Il33-deficient mice are highly susceptible to colitis and CAC. Mechanistically, we observed that IL-33 promoted IgA production from B cells, which is important for maintaining microbial homeostasis in the intestine. Il33-deficient mice developed a dysbiotic microbiota that was characterized by increased levels of mucolytic and colitogenic bacteria. In response to chemically induced colitis, this microbial landscape promoted the release of IL-1?, which acted as a critical driver of colitis and CAC. Consequently, reconstitution of symbiotic microbiota or IL-1? ablation markedly ameliorated colitis susceptibility in Il33-deficient animals. Our results demonstrate that IL-33 promotes IgA production to maintain gut microbial homoeostasis and restrain IL-1?-dependent colitis and CAC. This study therefore highlights modulation of IL-33, IgA, IL-1?, and the microbiota as a potential therapeutic approach in the treatment of IBD and CAC.
| S-EPMC5127671 | biostudies-literature
Project description:BackgroundIL-33 is a recently characterized IL-1 family cytokine and found to be expressed in inflammatory diseases, including severe asthma and inflammatory bowl disease. Recombinant IL-33 has been shown to enhance Th2-associated immune responses and potently increase mast cell proliferation and cytokine production. While IL-33 is constitutively expressed in endothelial and epithelial cells, where it may function as a transcriptional regulator, cellular sources of IL-33 and its role in inflammation remain unclear.Methodology/principal findingsHere, we identify mast cells as IL-33 producing cells. IgE/antigen activation of bone marrow-derived mast cells or a murine mast cell line (MC/9) significantly enhanced IL-33. Conversely, recombinant IL-33 directly activated mast cells to produce several cytokines including IL-4, IL-5 and IL-6 but not IL-33. We show that expression of IL-33 in response to IgE-activation required calcium and that ionomycin was sufficient to induce IL-33. In vivo, peritoneal mast cells expressed IL-33 and IL-33 levels were significantly lower within the skin of mast cell deficient mice, compared to littermate controls. Local activation of mast cells promotes edema, followed by the recruitment of inflammatory cells. We demonstrate using passive cutaneous anaphylaxis, a mast cell-dependent model, that deficiency in ST2 or antibody blockage of ST2 or IL-33 ablated the late phase inflammatory response but that the immediate phase response was unaffected. IL-33 levels in the skin were significantly elevated only during the late phase.Conclusions/significanceOur findings demonstrate that mast cells produce IL-33 after IgE-mediated activation and that the IL-33/ST2 pathway is critical for the progression of IgE-dependent inflammation.
| S-EPMC2914748 | biostudies-literature
Project description:BackgroundDespite the importance of inflammation in cancer, the role of the cytokine IL-33, and its receptor ST2, in colon cancer is unclear. The aim of this study was to investigate the role of IL-33, and its receptor isoforms (ST2 and ST2L), in colon cancer.MethodsSerum levels of IL-33 and sST2 were determined with ELISA. ST2 and IL-33 expression was detected with quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry. ST2 expression in CT26 cells was stably suppressed using ST2-specific shRNA. Cytokine and chemokine gene expression was detected with qRT-PCR.ResultsHuman colon tumours showed lower expression of ST2L as compared with adjacent non-tumour tissue (P<0.01). Moreover, the higher the tumour grade, the lower the expression of ST2L (P=0.026). Colon cancer cells expressed ST2 and IL-33 in vitro. Functional analyses showed that stimulation of tumour cells with IL-33 induced the expression of chemokine (C-C motif) ligand 2 (CCL2). Knockdown of ST2 in murine colon cancer cells resulted in enhanced tumour growth (P<0.05) in BALB/c mice in vivo. This was associated with a decrease in macrophage infiltration, with IL-33-induced macrophage recruitment reduced by antagonising CCL2 in vitro.ConclusionThe IL-33/ST2 signalling axis may have a protective role in colon carcinogenesis.
| S-EPMC4716545 | biostudies-literature
Project description:We have identified CD25high and CD25low ILC2 subsets in various mouse models of airway inflammation. Transcriptome analysis of acute IL-33 (CD25High) or chronic HDM (CD25Low) activated murine lung ILC2s suggests functional differences between these two ILC2 populations.
2020-05-13 | GSE99780 | GEO