Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes

Paračková, Zuzana; Vrabcová, Petra; Zentsová, Irena; Kayserová, Jana; Richtrova, I.; Sojka, Ludek; Stechova, Katerina; Šumnı́k, Zdenĕk; Šedivá, Anna

doi:10.1038/s41598-020-57507-8

Cited by 17 publications

(13 citation statements)

References 35 publications

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“…Table 6 summarizes the target gene - miRNA regulatory network and target gene - TF regulatory network (target genes, miRNAs and TFs) that were identified in the T1D, which included GRIN2B, EGFR, DKK1, GJA1, RGS4, TLN1, IGF2R, POLR2A, ARHGAP1, HIP1, RGS4, EYA1, CCL19, PRL, PRKACA, GAB2, HIP1, PXN , RGL2, hsa-mir-4257, hsa-mir-564, hsa-mir-587, hsa-mir-941, hsa-mir-561-3p, hsa-mir-4300, hsa-mir-5694, hsa-mir-378b, hsa-mir-3918, hsa-mir-6719-3p, FOXD1, GATA2, FOXL1, TP53, JUND, STAT3, TFAP2A, KLF5, PPARG and HINFP. STAT3 had been reported to be involved in the pathogenesis of T1D [ 81 ]. Polymorphic gene GATA2 has been reported to be crucial for the progression of coronary artery disease [ 82 ], but this gene might be responsible for advancement of T1D in patients with coronary artery disease.…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes related to the progression of type 1 diabetes by computational analysis

Prashanth

Vastrad²,

Tengli

et al. 2021

BMC Endocr Disord

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Background Type 1 diabetes (T1D) is a serious threat to childhood life and has fairly complicated pathogenesis. Profound attempts have been made to enlighten the pathogenesis, but the molecular mechanisms of T1D are still not well known. Methods To identify the candidate genes in the progression of T1D, expression profiling by high throughput sequencing dataset GSE123658 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and gene ontology (GO) and pathway enrichment analyses were performed. The protein-protein interaction network (PPI), modules, target gene - miRNA regulatory network and target gene - TF regulatory network analysis were constructed and analyzed using HIPPIE, miRNet, NetworkAnalyst and Cytoscape. Finally, validation of hub genes was conducted by using ROC (Receiver operating characteristic) curve and RT-PCR analysis. A molecular docking study was performed. Results A total of 284 DEGs were identified, consisting of 142 up regulated genes and 142 down regulated genes. The gene ontology (GO) and pathways of the DEGs include cell-cell signaling, vesicle fusion, plasma membrane, signaling receptor activity, lipid binding, signaling by GPCR and innate immune system. Four hub genes were identified and biological process analysis revealed that these genes were mainly enriched in cell-cell signaling, cytokine signaling in immune system, signaling by GPCR and innate immune system. ROC curve and RT-PCR analysis showed that EGFR, GRIN2B, GJA1, CAP2, MIF, POLR2A, PRKACA, GABARAP, TLN1 and PXN might be involved in the advancement of T1D. Molecular docking studies showed high docking score. Conclusions DEGs and hub genes identified in the present investigation help us understand the molecular mechanisms underlying the advancement of T1D, and provide candidate targets for diagnosis and treatment of T1D.

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Section: Discussionmentioning

confidence: 99%

Identification of hub genes related to the progression of type 1 diabetes by computational analysis

Prashanth

Vastrad²,

Tengli

et al. 2021

BMC Endocr Disord

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“…However, the contradictory effects of IL-27 have been reported in type 1 diabetes (T1D). Recent investigation reported that IL-27 not only showed immunomodulatory function, but also was a compensatory effort of dendritic cells against the ongoing inflammation in T1D patients (37). On the contrary, Ciecko et al (38) reported that IL-27 contributes to the pathogenesis of T1D in NOD mice by altering the balance of Treg and T H 1 cells and enhancing the effector function of CD8 T cells, although it was reported that serum IL-27 was strongly elevated in patients with SS (39), which is inconsistent with our results.…”

Section: Discussionmentioning

confidence: 99%

IL-27 Regulated CD4+IL-10+ T Cells in Experimental Sjögren Syndrome

Zhang

Tang

et al. 2020

Front. Immunol.

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Interleukin 27 (IL-27) plays diverse immune regulatory roles in autoimmune disorders and promotes the generation of IL-10-producing CD4 + T cells characterized by producing the immunosuppressive cytokine IL-10. However, whether IL-27 participates in pathological progress of Sjögren syndrome (SS) through regulating CD4 + IL-10 + T cells remains unknown. Here we aimed to explore the potential role of IL-27 and CD4 + IL-10 + T cells in the pathogenesis of SS. The IL-27 gene knockout non-obese diabetic (Il-27 −/− NOD) mice were generated and injected with exogenous IL-27. Exogenous injection of IL-27 and neutralization of IL-27 with anti-IL-27 antibody in NOD mice were performed. The histopathologic changes in submandibular glands, lacrimal glands and lung, salivary flow rate, and percentages of CD4 + IL-10 + T cells were determined. And, ovalbumin-immunized C57L/B6 mice were injected with IL-27 to detect the percentage of CD4 + IL-10 + T cells. In vitro, splenic naive T cells from C57L/B6 mice were cultured with IL-27 for 4 days to induce the differentiation of CD4 + IL-10 + T cells. In addition, IL-27, IL-10, and CD4 + IL-10 + T cells were determined in health control and SS patients. The results showed that Il-27 −/− NOD mice had more severe disease and lower level of CD4 + IL-10 + T cells than control mice. And IL-27 promoted the generation and differentiation of CD4 + IL-10 + T cells in vivo and in vitro significantly. In agreement with the findings in the SS-like mice, patients with SS showed lower levels of IL-27, IL-10, and CD4 + IL-10 + T cells. Our findings indicated that IL-27 deficiency aggravated SS by regulating CD4 + IL-10 + T cells. Targeting IL-27 and CD4 + IL-10 + T cells may be a novel therapy for patients with SS.

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“…Baptista et al [57] and Parackova et al [58] suggested that KIF1A and STAT3 were involved in progression of T1D. Polymorphic GATA2 gene plays a critical role in coronary artery disease [59], but this gene might be responsible for advancement of T1D with coronary artery disease.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of RNA-seq data revealed critical genes in type 1 diabetes and molecular docking studies

Prashanth¹,

Vastrad²,

Tengli³

et al. 2020

Preprint

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Background: Type 1 diabetes (T1D) is a serious threat to childhood life and has fairly complicated pathogenesis. Profound attempts have been made to enlighten the pathogenesis, but the molecular mechanisms of T1D are still not well known.Methods: To identify the candidate genes in the progression of T1D, Expression profiling by high throughput sequencing dataset GSE123658 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and gene ontology (GO) and pathway enrichment analyses were performed. The protein-protein interaction network (PPI), modules, target gene - miRNA regulatory network and target gene - TF regulatory network analysis were constructed and analyzed using HIPPIE, miRNet, NetworkAnalyst and Cytoscape. Finally, validation of hub genes was conducted by using ROC (Receiver operating characteristic) curve and RT-PCR analysis. Molecular docking studies were performed.Results: A total of 284 DEGs were identified, consisting of 142 up regulated genes and 142 down regulated genes. The gene ontology (GO) and pathways of the DEGs include cell-cell signaling, vesicle fusion, plasma membrane, signaling receptor activity, lipid binding, signaling by GPCR and innate immune system. Four hub genes were identified and biological process analysis revealed that these genes were mainly enriched in cell-cell signaling, cytokine signaling in immune system, signaling by GPCR and innate immune system. ROC curve and RT-PCR analysis showed that EGFR, GRIN2B, POLR2A and PRKACA might be involved in the advancement of T1D. Molecular docking studies showed high docking score.Conclusions: DEGs and hub genes identified in the present investigation help us understand the molecular mechanisms underlying the advancement of T1D, and provide candidate targets for diagnosis and treatment of T1D.

show abstract

Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes

Cited by 17 publications

References 35 publications

Identification of hub genes related to the progression of type 1 diabetes by computational analysis

Identification of hub genes related to the progression of type 1 diabetes by computational analysis

IL-27 Regulated CD4+IL-10+ T Cells in Experimental Sjögren Syndrome

Bioinformatics analysis of RNA-seq data revealed critical genes in type 1 diabetes and molecular docking studies

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