IL-22 Enhances TNF-α- and IL-1-Induced CXCL8 Responses by Intestinal Epithelial Cell Lines

Young, Rebecca S.; Wiles, Brody M; McGee, Dennis W.

doi:10.1007/s10753-017-0614-5

Cited by 13 publications

(13 citation statements)

References 24 publications

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“…IL-1β is an important pro-inflammatory cytokine that promotes the inflammatory process and coordinates autoimmune responses (Ligumsky et al, 1990). IL-1β is correlated with disease severity, implying essential in pathogenesis of IBD (McAlindon et al, 1998;Young et al, 2017). Stimulated by microbe-associated molecular patterns (MAMPs), IL-1β from macrophages, DCs, and epithelial cells induces the development of CD4 + T cells (de Souza and Fiocchi, 2016).…”

Section: Discussionmentioning

confidence: 99%

Identification of Immune Cell Landscape and Construction of a Novel Diagnostic Nomogram for Crohn’s Disease

Chen

Yuan

et al. 2020

Front. Genet.

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Crohn's disease (CD) has an increasing incidence and prevalence worldwide. The etiology of CD remains unclear and there is no gold standard for diagnosis. The dysregulated immune response and different infiltration status of immune cells are critical for CD pathogenesis; therefore, it is important to provide an overview of immunecell alterations in CD and explore a novel method for auxiliary diagnosis. Here we analyzed microarray datasets from Gene Expression Omnibus (GEO), and an extended version of Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORTx) was utilized to estimate the fraction of 22 types of immune cells. Differentially expressed genes (DEGs) and a protein-protein interaction (PPI) network were identified, and we performed gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) to identify differentially regulated pathways in CD. Least absolute shrinkage and selection operator (LASSO) regression was conducted to filter features, and a diagnostic nomogram based on logistic regression was built and validated in an independent validation cohort. In the derivation cohort, we found a proportion of 17 immune-cell types to be significantly altered between CD and healthy controls and a total of 150 DEGs were identified, which were mostly related to the immune response. Among the 15 hub genes based on the PPI network, C-X-C chemokine ligand 8 (CXCL8) and interleukin-1B (IL-1B) showed the highest degree of interaction. Additionally, GSEA and GSVA identified five significantly enriched pathways, among which the nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway was critical in the CD development. Furthermore, six variables comprising of CXCL8, IL-1B, M1 macrophages, regulatory T cells, CD8 + T cells, and plasma cells were identified by LASSO regression and incorporated into a logistic regression model. The nomogram displayed a good prediction, with a 0.915 area under the receiver operating curve (AUC) and a C-index of 0.915 [95% confidence interval (CI): 0.875-0.955]. Similar results were found in the validation cohort, with an AUC of 0.884 and a 0.884 C-index (95% CI: 0.843-0.924). These results provide novel in silico insight into cellular and molecular characteristics of CD and potential biomarkers for diagnosis and targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Identification of Immune Cell Landscape and Construction of a Novel Diagnostic Nomogram for Crohn’s Disease

Chen

Yuan

et al. 2020

Front. Genet.

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“…Therefore, the inhibition of the NF-κB signaling pathway may be an important factor in reducing intestinal mucosal damage. IL-1β, IL-6, and TNF-α are vital pro-inflammatory cytokines that widely affect the inflammatory process[ 38 - 40 ]. IL-1β and TNF-α have been reported to exhibit a synergistic effect on the activation of the NF-κB pathway and inflammation[ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Wumei pills attenuates 5-fluorouracil-induced intestinal mucositis through Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB pathway and microbiota regulation

Lyu¹,

Liu²,

Wu³

et al. 2022

WJG

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BACKGROUND Radiotherapy and chemotherapy can kill tumor cells and improve the survival rate of cancer patients. However, they can also damage normal cells and cause serious intestinal toxicity, leading to gastrointestinal mucositis[ 1 ]. Traditional Chinese medicine is effective in improving the side effects of chemotherapy. Wumei pills (WMP) was originally documented in the Treatise on Exogenous Febrile Diseases. It has a significant effect on chronic diarrhea and other gastrointestinal diseases, but it is not clear whether it affects chemotherapy-induced intestinal mucositis (CIM). AIM To explore the potential mechanism of WMP in the treatment of CIM through experimental research. METHODS We used an intraperitoneal injection of 5-fluorouracil (5-Fu) to establish a CIM mouse model and an oral gavage of WMP decoction (11325 and 22650 mg/kg) to evaluate the efficacy of WMP in CIM. We evaluated the effect of WMP on CIM by observing the general conditions of the mice (body weight, food intake, spleen weight, diarrhea score, and hematoxylin and eosin stained tissues). The expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and myeloperoxidase (MPO), as well as the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB (TLR4/MyD88/NF-κB) signaling pathway proteins and tight junction proteins (zonula occludens-1, claudin-1, E-cadherin, and mucin-2) was determined. Furthermore, intestinal permeability, intestinal flora, and the levels of short-chain fatty acids (SCFA) were also assessed. RESULTS WMP effectively improved the body weight, spleen weight, food intake, diarrhea score, and inflammatory status of the mice with intestinal mucositis, which preliminarily confirmed the efficacy of WMP in CIM. Further experiments showed that in addition to reducing the levels of TNF-α, IL-1β, IL-6, and MPO and inhibiting the expression of the TLR4/MyD88/NF-κB pathway proteins, WMP also repaired the integrity of the mucosal barrier of mice, regulated the intestinal flora, and increased the levels of SCFA (such as butyric acid). CONCLUSION WMP can play a therapeutic role in CIM by alleviating inflammation, restoring the mucosal barrier, and regulating gut microbiota.

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“…The upregulation of IL1R1 by IL-22 in the HT-29 cells was identified in the initial experiments and further explored for its potential to alter the gene expression patterns in the target cells. Previously, HT-29 cells were shown to produce significantly increased levels of CXCL8 protein in the presence of IL-22 and TNF-α or IL-1β compared to those with TNF-α or IL-1β alone [ 38 ], where the authors suggest that the angiogenesis-enhancing capacity of CXCL8 may contribute to the role of IL-22 in wound-healing responses. In the current study, the combination of IL-22 and IL-1β generated an altered gene expression pattern compared to IL-22 in the absence of IL-1β ( Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of an IL-22-Dependent Gene Signature as a Pharmacodynamic Biomarker

Rae¹,

Hackney²,

Huang³

et al. 2021

IJMS

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Interleukin-22 (IL-22) plays a role in epithelial barrier function and repair, and may provide benefits in conditions like inflammatory bowel disease. However, limited human data are available to assess the clinical effect of IL-22 administration. This study used a human intestinal cell line to identify an IL-22-dependent gene signature that could serve as a pharmacodynamic biomarker for IL-22 therapy. The response to IL-22Fc (UTTR1147A, an Fc-stabilized version of IL-22) was assessed in HT-29 cells by microarray, and the selected responsive genes were confirmed by qPCR. HT-29 cells demonstrated dose-dependent increases in STAT3 phosphorylation and multiple gene expression changes in response to UTTR1147A. Genes were selected that were upregulated by UTTR1147A, but to a lesser extent by IL-6, which also signals via STAT3. IL-1R1 was highly upregulated by UTTR1147A, and differential gene expression patterns were observed in response to IL-22Fc in the presence of IL-1β. An IL-22-dependent gene signature was identified that could serve as a pharmacodynamic biomarker in intestinal biopsies to support the clinical development of an IL-22 therapeutic. The differential gene expression pattern in the presence of IL-1β suggests that an inflammatory cytokine milieu in the disease setting could influence the clinical responses to IL-22.

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IL-22 Enhances TNF-α- and IL-1-Induced CXCL8 Responses by Intestinal Epithelial Cell Lines

Cited by 13 publications

References 24 publications

Identification of Immune Cell Landscape and Construction of a Novel Diagnostic Nomogram for Crohn’s Disease

Identification of Immune Cell Landscape and Construction of a Novel Diagnostic Nomogram for Crohn’s Disease

Wumei pills attenuates 5-fluorouracil-induced intestinal mucositis through Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB pathway and microbiota regulation

Identification of an IL-22-Dependent Gene Signature as a Pharmacodynamic Biomarker

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