Notch and TNF-α signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients

Kuno, Reiko; Ito, Go; Kawamoto, Ami; Hiraguri, Yui; Sugihara, Hady Yuki; Takeoka, Sayaka; Nagata, Sayaka; Takahashi, Junichi; Tsuchiya, Mao; Anzai, Sho; Mizutani, Tomohiro; Shimizu, Hiromichi; Yui, Satoru; Tsuchiya, Kiichiro; Watanabe, Mamoru; Okamoto, Ryuichi

doi:10.1016/j.bbrep.2020.100906

Cited by 15 publications

(16 citation statements)

References 22 publications

(26 reference statements)

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“…The regenerative gene (REG) family shows increased expression during IBD-associated inflammation (Xu et al, 2019). OLFM4 secreted by human intestinal epithelial cells is upregulated in the inflamed mucosa of IBD patients; however, its functional role in IBD has remained uncertain (Kuno et al, 2021). DMBT1 gene, which is considered as a candidate tumor suppressor gene for the brain, lungs, stomach, and colorectal cancers, has shown an increased expression in inflamed tissues of IBD patients, and it has been stated that impaired DMBT1 function may be associated with the onset of Crohn's disease (Renner et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

Mapping Transcriptome Data to Protein–Protein Interaction Networks of Inflammatory Bowel Diseases Reveals Disease-Specific Subnetworks

Maden

Acuner-Ozbabacan

2021

Front. Genet.

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Inflammatory bowel disease (IBD) is the common name for chronic disorders associated with the inflammation of the gastrointestinal tract. IBD is triggered by environmental factors in genetically susceptible individuals and has a significant number of incidences worldwide. Crohn’s disease (CD) and ulcerative colitis (UC) are the two distinct types of IBD. While involvement in ulcerative colitis is limited to the colon, Crohn’s disease may involve the whole gastrointestinal tract. Although these two disorders differ in macroscopic inflammation patterns, they share various molecular pathogenesis, yet the diagnosis can remain unclear, and it is important to reveal their molecular signatures in the network level. Improved molecular understanding may reveal disease type-specific and even individual-specific targets. To this aim, we determine the subnetworks specific to UC and CD by mapping transcriptome data to protein–protein interaction (PPI) networks using two different approaches [KeyPathwayMiner (KPM) and stringApp] and perform the functional enrichment analysis of the resulting disease type-specific subnetworks. TP63 was identified as the hub gene in the UC-specific subnet and p63 tumor protein, being in the same family as p53 and p73, has been studied in literature for the risk associated with colorectal cancer and IBD. APP was identified as the hub gene in the CD-specific subnet, and it has an important role in the pathogenesis of Alzheimer’s disease (AD). This relation suggests that some similar genetic factors may be effective in both AD and CD. Last, in order to understand the biological meaning of these disease-specific subnets, they were functionally enriched. It is important to note that chemokines—special types of cytokines—and antibacterial response are important in UC-specific subnets, whereas cytokines and antimicrobial responses as well as cancer-related pathways are important in CD-specific subnets. Overall, these findings reveal the differences between IBD subtypes at the molecular level and can facilitate diagnosis for UC and CD as well as provide potential molecular targets that are specific to disease subtypes.

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Section: Resultsmentioning

confidence: 99%

Mapping Transcriptome Data to Protein–Protein Interaction Networks of Inflammatory Bowel Diseases Reveals Disease-Specific Subnetworks

Maden

Acuner-Ozbabacan

2021

Front. Genet.

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“…Moreover, OLFM4 was increased after five rounds of damage. OLFM4 is a Notch target gene ( Van-Dussen et al, 2012) and a key marker of colorectal cancer (Neyazi et al, 2021;Okamoto et al, 2021) and is elevated in IBD subjects (Gersemann et al, 2012;Kuno et al, 2021;Suzuki et al, 2018). Overall, these data suggest an impairment in WNT signaling and self-renewal that may be driven by OLFM4 + cells (Huch et al, 2013;Shimokawa et al, 2017;Yan et al, 2017;Ye et al, 2020).…”

Section: Discussionmentioning

confidence: 95%

An in vitro chronic damage model impairs inflammatory and regenerative responses in human colonoid monolayers

et al. 2022

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“…Kuno et al showed that OLFM4 secretion led to antimicrobial activity, while cytoplasmic OLFM4 played an anti-apoptotic role in human intestinal epithelial cells. 11 Therefore, the OLFM4 producing cell type needs to be clarified in order to determine the role of OLFM4 in sepsis-related ARDS. Subsequently, cell type-specific OLFM4 knockout model can be constructed to explore the detailed mechanism of OLFM4 in sepsis-related ARDS.…”

Section: Discussionmentioning

confidence: 99%

OLFM4 Regulates Lung Epithelial Cell Function in Sepsis-Associated ARDS/ALI via LDHA-Mediated NF-κB Signaling

Gong¹,

Li²,

Zheng³

et al. 2021

JIR

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Background Acute respiratory distress syndrome (ARDS) is one of the leading causes of death in patients with sepsis. As such, early and accurate identification of sepsis-related ARDS is critical. Methods Bioinformatic analysis was used to explore the GEO datasets. ELISA method was used to detect the plasma or cellular supernatant of relevant proteins. Quantitative real-time PCR was used for mRNA measurements and Western blot was applied for protein measurements. Immunohistochemistry staining and Immunofluorescence staining were used to identify the localization of OLFM4. Cecal ligation and puncture (CLP) model was used to establish sepsis model. Results The bioinformatic analysis results identified ten genes ( CAMP, LTF, RETN, LCN2, ELANE, PGLYRP1, BPI, DEFA4, MPO , and OLFM4 ) as critical in sepsis and sepsis-related ARDS. OLFM4, LCN2 , and BPI were further demonstrated to have diagnostic values in sepsis-related ARDS. Plasma expression of OLFM4 and LCN2 was also upregulated in sepsis-related ARDS patients compared to septic patients alone. OLFM4 expression was significantly increased in the lung tissues of septic mice and was co-localized with Ly6G+ neutrophils, F4/80+ macrophages and pro-surfactant C+ lung epithelial cells. In vitro data showed that OLFM4 expression in lung epithelial cells was downregulated upon LPS stimulation, whereas neutrophil media induced OLFM4 expression in lung epithelial cells. Overexpression of OLFM4 and treatment with recombinant OLFM4 effectively suppressed LPS-induced pro-inflammatory responses in lung epithelial cells. Furthermore, the increased levels of LDHA phosphorylation and the downstream NF-κB activation induced by LPS in epithelial cells were effectively diminished by OLFM4 overexpression and recombinant OLFM4 treatment via a reduction in ROS production and HIF1α expression. Conclusion OLFM4 may regulate the pro-inflammatory response of lung epithelial cells in sepsis-related ARDS by modulating metabolic disorders; this result could provide new insights into the treatment of sepsis-induced ARDS.

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Notch and TNF-α signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients

Cited by 15 publications

References 22 publications

Mapping Transcriptome Data to Protein–Protein Interaction Networks of Inflammatory Bowel Diseases Reveals Disease-Specific Subnetworks

Mapping Transcriptome Data to Protein–Protein Interaction Networks of Inflammatory Bowel Diseases Reveals Disease-Specific Subnetworks

An in vitro chronic damage model impairs inflammatory and regenerative responses in human colonoid monolayers

OLFM4 Regulates Lung Epithelial Cell Function in Sepsis-Associated ARDS/ALI via LDHA-Mediated NF-κB Signaling

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