Journal articles on the topic 'IL32'
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Decombis, Salome, Antonin Papin, Celine Bellanger, Clara Sortais, Christelle Dousset, Yannick Le Bris, Stephanie Blandin, et al. "The IL32/BAFF Axis Supports Prosurvival Dialog in the Lymphoma Ecosystem and Is Disrupted By NIK Inhibition." Blood 138, Supplement 1 (November 5, 2021): 781. http://dx.doi.org/10.1182/blood-2021-144839.
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Abstract Background Aggressive B-cell lymphomas, such as Mantle cell lymphoma (MCL), are microenvironment-dependent tumors but, in contrast to tumoral intrinsic anomalies, complex interplays within their ecosystems are largely ignored. A better understanding of these dialogs could provide new perspectives integrating the key role of the microenvironment to increase treatment efficiency of this hard to cure B-cell malignancy. Methods To identify novel molecular regulations occurring in lymphoma protective ecosystems, we performed a transcriptomic analysis based on the comparison of publicly available datasets from circulating (PB, n=77) versus MCL lymph nodes (LN, n=107) together with deep RNA sequencing of purified CD19+CD5+ MCL (n=8) versus normal B-cells (n=6). This integrated analysis led to the discovery of microenvironment-dependent and tumor-specific secretion of the cytokine IL32β by lymphoma cells. Using in situ multiplex immunohistochemistry , ex vivo models of primary MCL cells (n=23) and IL32 KO MCL cell lines (Crispr/Cas9), we studied the regulation and the functional impact of IL32β in the MCL context, especially in the dialog with tumor-associated macrophages. Results Among the 6887 genes differentially expressed in MCL LN compared to PB in vivo, 70% were confirmed in CD19+ MCL cells cocultured ex vivo and 39% were tumor-specific, that is to say not upregulated in cocultured normal B cells (NBC). Top-genes scoring revealed that IL32 was the most upregulated genes within the "Tumor-specific" transcriptional program. Using ex vivo models of primary MCL cells, we demonstrated that the microenvironment-dependent secretion of IL32β was controlled by the CD40/NFKB2 axis whereas its tumor specificity was the consequence of IL32 promoter hypomethylation in MCL compared to NBC. IL32 protein expression was confirmed in MCL LN in situ by multiplex IHC. The latter allowed the concurrent detection of MCL cells, T cells, macrophages and IL32. Consistently with the microenvironment-dependent induction of IL32 in MCL, we observed that IL32 expression was enriched in situ in tumor zones infiltrated with T cells, compared to tumor-exclusive zones. Based on in vitro experiments using IL32 KO MINO cells (Crispr/Cas9), we demonstrated that, through the secretion of IL32β, the tumor was able to corrupt its microenvironment by polarizing monocytes into specific protumoral CD163 mid MCL-associated macrophages, which secrete both pro- (e.g. IL6, OSM, IL1a/b) and anti- inflammatory (e.g. IL10, IDO, IL18, IL4L1) soluble factors. We next highlighted that IL32β-stimulated macrophages supported tumor survival mostly through a soluble dialog, which is driven by BAFF. Finally, we demonstrated the efficacy of selective NIK/alternative-NFkB inhibition to counteract both microenvironment-dependent induction of IL32β (RNA expression inhibition: 62 % ; n= 3) and BAFF-dependent survival of MCL cells (survival support inhibition : 47 % ; n=6). Conclusions In summary, our data uncovered the IL32β/BAFF axis as a previously undescribed pathway involved in MCL-associated macrophage polarization and tumor survival. Dependent on alternative-NFkB signaling, tumor-specific secretion of IL32β led to the corruption of the microenvironment through the polarization of monocytes into specific MCL-associated macrophages, which in turn favor tumor survival. While IL32β-stimulated macrophages secreted several protumoral factors, they supported MCL survival through BAFF and consequent alternative-NFkB activation in tumor cells. Our data shows that targeting IL32b, BAFF or the alternative NFkB pathway through NIK inhibition could also be of major interest for counteracting the multiple cross-talks that occur in the MCL microenvironment and, especially, the CD40L + T-cell / MCL / CD163 + MCL-associated macrophage triad. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Lu, Huili, Wei Han, Abdulgabar Salama, and Anja Moldenhauer. "CXCL9 and IL32 Regulate Progenitor Expansion and Protect Hematopoietic Progenitor Cells From Chemotherapy." Blood 118, no. 21 (November 18, 2011): 1316. http://dx.doi.org/10.1182/blood.v118.21.1316.1316.
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Abstract Abstract 1316 Background: We have reported that the cytokines CXCL9 and IL32 regulate murine bone marrow regeneration post chemotherapy, but the reasons for this effect and whether they work directly on progenitor cells remain unclear. Methods: Human CD34+ cells from cord blood were incubated with CXCL9 or IL32. Cell numbers were determined on a weekly basis, and one-week expanded cells were seeded on top of a confluent MS-5 stroma cell layer to determine the number of cobblestone-area forming and long-term culture initiating cells (LTC-IC). Apoptosis rates after incubation with CXCL9/IL32 and SCF/G-CSF/IL3 prior to Ara-C treatment (300mM, 1 h) were assessed by Annexin V detection. Subsequently, signaling pathways after stimulation with IL32 or CXCL9 were examined using the luminex map technology. Results: CXCL9 did not influence CD34+ cell expansion, while IL32 enhanced the expansion rates significantly [6.69±1.38 versus to 3.57±0.70 fold in the control group, p<0.05]. However, more LTC-ICs after CXCL9 treatment (1357±123 of CXCL9 group versus 1081±119 of control group, p<0.05) were found, while IL32 reduced the number of LTC-ICs (78±8 of IL32 group, p<0.005). That suggests that CXCL9 kept more primitive LTC-ICs quiescent instead of entering expansion during the one-week incubation, while IL32 rather stimulated the differentiation of LTC-ICs. Since SCF, G-CSF and IL-3 are the most widely used hematopoietic growing factors (HGF) in stem cell expansion, we detected their roles during chemotherapeutical treatment in vitro. We observed enhanced apoptosis during Ara-C treatment when the cells were incubated with SCF or IL3. But when CXCL9 or IL32 were added, results were different. Both CXCL9 and IL-32 reduced the apoptosis rate resulting from Ara-C treatment, when SCF is present (26.37±1.12% of CXCL9+SCF group, 29.97±0.72% of IL32+SCF group, versus 35.52±1.21% of SCF alone, p <0.005 and p<0.05), but none of them affected IL-3 related apoptosis. Especially the effect of CXCL9 was inhibited using antibodies to its receptor CXCR3 (37.97±1.50% with anti-CXCR3 versus 35.52±1.21% of SCF alone, p= 0.09, versus 26.37±1.12% of CXCL9+SCF group p<0.05). G-CSF alone did not influence Ara-C induced apoptosis, but in combination with IL32 the apoptosis rate increased (23.37±0.09% of IL32+G-CSF versus 19.59±0.79% of G-CSF alone, p<0.005). That suggests that IL32 could regulate stem cell expansion differently through various pathways in collaboration with SCF and G-CSF. In fact, IL32 reduced STAT5 and p38 activity, while CXCL9 activated p38 and JNK pathways of CD34+ cells in combination with SCF. Conclusions: Our results demonstrate that both CXCL9 and IL32 can regulate stem cell expansion in vitro; CXCL9 could protect HPCs from chemotherapy and therefore support the following recovery, IL32 could help progenitor cells to expand, differentiate rapidly and thereby enhance the regeneration of the hematologic system. Disclosures: No relevant conflicts of interest to declare.
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Kang, Ji Young, and Kyung Eun Kim. "Prognostic Value of Interleukin-32 Expression and Its Correlation with the Infiltration of Natural Killer Cells in Cutaneous Melanoma." Journal of Clinical Medicine 10, no. 20 (October 13, 2021): 4691. http://dx.doi.org/10.3390/jcm10204691.
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Interleukin-32 (IL-32) is well known as a proinflammatory cytokine that is expressed in various immune cells and cancers. However, the clinical relevance of IL-32 expression in cutaneous melanoma has not been comprehensively studied. Here, we identified the prognostic value of IL32 expression using various systematic multiomic analyses. The IL32 expressions were significantly higher in cutaneous melanoma than in normal tissue, and Kaplan–Meier survival analysis showed a correlation between IL32 expression and good prognosis in cutaneous melanoma patients. In addition, we analyzed the correlation between IL32 expression and the infiltration of natural killer (NK) cells to identify a relevant mechanism between IL32 expression and prognosis in cutaneous melanoma (p = 0.00031). In the relationship between IL32 expression and the infiltration of NK cells, a negative correlation was found in resting NK cells (rho = −0.38, p = 3.95 × 10−17) whereas a strong positive correlation was observed only in active NK cells (rho = 0.374, p = 1.23 × 10−16). Moreover, IL32 expression was markedly positively correlated with the cytolytic molecules, such as granzyme and perforin. These data suggest that IL32 expression may increase patient survival through the infiltration and activation of NK cells, representative anticancer effector cells, in cutaneous melanoma. Collectively, this study provides the prognostic value of IL32 expression and its potential role as an effective predictive biomarker for NK cell infiltration in cutaneous melanoma.
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Baselli, Guido Alessandro, Paola Dongiovanni, Raffaela Rametta, Marica Meroni, Serena Pelusi, Marco Maggioni, Sara Badiali, et al. "Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker." Gut 69, no. 10 (January 30, 2020): 1855–66. http://dx.doi.org/10.1136/gutjnl-2019-319226.
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ObjectiveEfforts to manage non-alcoholic fatty liver disease (NAFLD) are limited by the incomplete understanding of the pathogenic mechanisms and the absence of accurate non-invasive biomarkers. The aim of this study was to identify novel NAFLD therapeutic targets andbiomarkers by conducting liver transcriptomic analysis in patients stratified by the presence of the PNPLA3 I148M genetic risk variant.DesignWe sequenced the hepatic transcriptome of 125 obese individuals. ‘Severe NAFLD’ was defined as the presence of steatohepatitis, NAFLD activity score ≥4 or fibrosis stage ≥2. The circulating levels of the most upregulated transcript, interleukin-32 (IL32), were measured by ELISA.ResultsCarriage of the PNPLA3 I148M variant correlated with the two major components of hepatic transcriptome variability and broadly influenced gene expression. In patients with severe NAFLD, there was an upregulation of inflammatory and lipid metabolism pathways. IL32 was the most robustly upregulated gene in the severe NAFLD group (adjusted p=1×10−6), and its expression correlated with steatosis severity, both in I148M variant carriers and non-carriers. In 77 severely obese, and in a replication cohort of 160 individuals evaluated at the hepatology service, circulating IL32 levels were associated with both NAFLD and severe NAFLD independently of aminotransferases (p<0.01 for both). A linear combination of IL32-ALT-AST showed a better performance than ALT-AST alone in NAFLD diagnosis (area under the curve=0.92 vs 0.81, p=5×10−5).ConclusionHepatic IL32 is overexpressed in NAFLD, correlates with hepatic fat and liver damage, and is detectable in the circulation, where it is independently associated with the presence and severity of NAFLD.
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Gautam, Anuradha, and Bhaswati Pandit. "IL32: The multifaceted and unconventional cytokine." Human Immunology 82, no. 9 (September 2021): 659–67. http://dx.doi.org/10.1016/j.humimm.2021.05.002.
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Logan, Jeongok G., Sijung Yun, Yongde Bao, Emily Farber, and Charles R. Farber. "RNA-sequencing analysis of differential gene expression associated with arterial stiffness." Vascular 28, no. 5 (May 6, 2020): 655–63. http://dx.doi.org/10.1177/1708538120922650.
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Objectives Arterial stiffness is recognized as an important predictor of cardiovascular disease morbidity and mortality, independent of traditional cardiovascular disease risk factors. Given that arterial tissue is not easily accessible, most gene expression studies on arterial stiffness have been conducted on animals or on patients who have undergone by-pass surgeries. In order to obtain a deeper understanding of early changes of arterial stiffness, this study compared transcriptome profiles between healthy adults with higher and lower arterial stiffness. Methods The sample included 20 healthy female adults without cardiovascular disease. Arterial stiffness was measured by carotid-femoral pulse wave velocity, the “gold-standard” measure of central arterial stiffness. Peripheral blood samples collected to PAXgene™ RNA tubes were used for RNA sequencing (RNA-seq). The potential confounding effects of age, body mass index, and mean arterial pressure were controlled for in RNA-seq analysis. To validate RNA-seq results, quantitative real-time PCR (qRT-PCR) was performed for six selected genes. Results The findings demonstrated that genes including CAPN9, IL32, ERAP2, RAB6B, MYBPH, and miRNA626 were down-regulated, and that MOCS1 gene was up-regulated among the people with higher arterial stiffness. Real-time PCR showed that the changes of CAPN9, IL32, ERAP2, and RAB6B were in concordance with RNA-seq data, and confirmed the validity of the gene expression profiles obtained by RNA-seq analysis. Conclusions Previous studies have suggested the potential roles of CAPN9, IL32, and ERAP2 in structural changes of the arterial wall through up-regulation of metalloproteinases. However, the current study showed that CAPN9, IL32, and ERAP2 were down-regulated in the individuals with higher arterial stiffness, compared with those with lower arterial stiffness. The unexpected directions of expression of these genes may indicate an effort to maintain vascular homeostasis during increased arterial stiffness among healthy individuals. Further studies are guaranteed to investigate the roles of CAPN9, IL32, and ERAP2 in regulating arterial stiffness in people with and without cardiovascular disease.
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Diakowska, Dorota, and Małgorzata Krzystek-Korpacka. "Local and Systemic Interleukin-32 in Esophageal, Gastric, and Colorectal Cancers: Clinical and Diagnostic Significance." Diagnostics 10, no. 10 (October 4, 2020): 785. http://dx.doi.org/10.3390/diagnostics10100785.
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Little is known on clinical and diagnostic relevance of interleukin-32 in gastrointestinal tract (GIT) cancers. We determined its mRNA (n = 52) and protein (n = 63) expression in paired (tumor-normal) samples from esophageal squamous cell carcinoma (ESCC) and gastric (GC) and colorectal cancer (CRC) patients, with reference to cancer-associated genes, and quantified circulating interleukin-32 in 70 cancer patients and 28 controls. IL32 expression was significantly upregulated solely in ESCC, reflecting T stage in non-transformed tumor-adjacent tissue. Fold-change in IL32 and IL-32 was higher in left-sided CRC, owing to high interleukin expression in non-transformed right-sided colonic mucosa. IL32 was independently and positively associated with Ki67, HIF1A, and ACTA2 and negatively with TJP1 in tumors and with IL10Ra and BCLxL in non-transformed tumor-adjacent tissue. IL-32 protein was significantly upregulated in colorectal tumors. In ESCC, advanced stage and lymph node metastasis were associated with significant IL-32 upregulation. Circulating interleukin was significantly elevated in cancer patients, more so in ESCC and GC than CRC. As biomarker, IL-32 detected gastroesophageal cancers with 99.5% accuracy. In conclusion, IL-32 is upregulated in GIT cancers at local and systemic level, reflecting hypoxia and proliferative and invasive/metastatic capacity in tumors and immunosuppressive and antiapoptotic potential in non-transformed mucosa, while being an accurate biomarker of gastroesophageal cancers.
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Ramirez-Carracedo, Rafael, Laura Tesoro, Ignacio Hernandez, Javier Diez-Mata, David Piñeiro, Macarena Hernandez-Jimenez, Jose Luis Zamorano, and Carlos Zaragoza. "Targeting TLR4 with ApTOLL Improves Heart Function in Response to Coronary Ischemia Reperfusion in Pigs Undergoing Acute Myocardial Infarction." Biomolecules 10, no. 8 (August 9, 2020): 1167. http://dx.doi.org/10.3390/biom10081167.
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Toll-like receptor 4 (TLR4) contributes to the pathogenesis of coronary ischemia/reperfusion (IR). To test whether the new TLR4 antagonist, ApTOLL, may prevent coronary IR damage, we administered 0.078 mg/kg ApTOLL or Placebo in pigs subjected to IR, analyzing the levels of cardiac troponins, matrix metalloproteinases, pro-, and anti-inflammatory cytokines, heart function, and tissue integrity over a period of 7 days after IR. Our results show that ApTOLL reduced cardiac troponin-1 24 h after administration, improving heart function, as detected by a significant recovery of the left ventricle ejection fraction (LVEF) and the shortening fraction (FS) cardiac parameters. The extension of necrotic and fibrotic areas was also reduced, as detected by Evans blue/2,3,5-triphenyltetrazolium chloride (TTC) staining, Hematoxylin/Eosine, and Masson Trichrome staining of heart sections, together with a significant reduction in the expression of the extracellular matrix-degrading, matrix metalloproteinase 9. Finally, the expression of the following cytokines, CCL1, CCL2, MIP1-A-B, CCL5, CD40L, C5/C5A, CXCL1, CXCL10, CXCL11, CXCL12, G-CSF, GM-CSF, ICAM-1, INF-g, IL1-a, ILI-b, IL-1Ra, IL2, IL4, IL5, IL6, IL8, IL10, IL12, IL13, IL16, IL17-A, IL17- E, IL18, IL21, IL27, IL32, MIF, SERPIN-E1, TNF-a, and TREM-1, were also assayed, detecting a pronounced decrease of pro-inflammatory cytokines after 7 days of treatment with ApTOLL. Altogether, our results show that ApTOLL is a promising new tool for the treatment of acute myocardial infarction (AMI).
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Poma, Anello Marcello, Angelo Genoni, Francesco Broccolo, Maria Denaro, Alberto Pugliese, Fulvio Basolo, and Antonio Toniolo. "Immune Transcriptome of Cells Infected with Enterovirus Strains Obtained from Cases of Type 1 Diabetes." Microorganisms 8, no. 7 (July 12, 2020): 1031. http://dx.doi.org/10.3390/microorganisms8071031.
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Enterovirus (EV) infection of insulin-producing pancreatic beta cells is associated with type 1 diabetes (T1D), but little is known about the mechanisms that lead the virus to cause a persistent infection and, possibly, to induce beta cell autoimmunity. A cell line susceptible to most enterovirus types was infected with EV isolates from cases of T1D and, for comparison, with a replication-competent strain of coxsackievirus B3. The transcription of immune-related genes and secretion of cytokines was evaluated in infected vs. uninfected cells. Acutely infected cells showed the preserved transcription of type I interferon (IFN) pathways and the enhanced transcription/secretion of IL6, IL8, LIF, MCP1, and TGFB1. On the other hand, infection by defective EV strains obtained from diabetic subjects suppressed IFN pathways and the transcription of most cytokines, while enhancing the expression of IL8, IL18, IL32, and MCP1. IL18 and IL32 are known for their pathogenic role in autoimmune diabetes. Thus, the cytokine profile of AV3 cells infected by diabetes-derived EV strains closely matches that observed in patients at the early stages of T1D. The concordance of our results with clinically verified information reinforces the hypothesis that the immune changes observed in type 1 diabetic patients are due to a hardly noticeable virus infection.
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Wang, Anna, Hongyan Guo, and Zaiqiu Long. "Integrative Analysis of Differently Expressed Genes Reveals a 17-Gene Prognosis Signature for Endometrial Carcinoma." BioMed Research International 2021 (July 14, 2021): 1–18. http://dx.doi.org/10.1155/2021/4804694.
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Endometrial carcinoma (EC) is the fifth widely occurring malignant neoplasm among women all over the world. However, there is still lacking efficacy indicators for EC’s prognosis. Here, we analyzed two databases including an RNA-sequencing-based TCGA dataset and a microarray-based GSE106191. After normalizing the raw data, we identified 114 common genes with upregulation and 308 common genes with downregulation in both the TCGA and GSE106191 databases. Bioinformatics analysis showed that the differently expressed genes in EC were related to the IL17 signaling pathway, PI3K-Akt signaling pathway, and cGMP-PKG signaling pathway. Furthermore, we performed the least absolute shrinkage and selection operator (LASSO) Cox regression analysis and generated a signature featuring 17 prognosis-related genes (MAL2, ANKRD22, METTL7B, IL32, ERFE, OAS1, TRPC1, SRPX, RAPGEF4, PSD3, SIMC1, TRPC6, WFS1, PGR, PAMR1, KCNK6, and FAM189A2) and found that it could predict OS in EC patients. The further analysis showed that OAS1, MAL2, ANKRD22, METTL7B, and IL32 were significantly upregulated in EC samples after comparison with normal samples. However, TRPC1, SRPX, RAPGEF4, PSD3, SIMC1, TRPC6, WFS1, PGR, PAMR1, KCNK6, and FAM189A2 were significantly downregulated in EC samples in comparison with normal samples. And correlation analysis showed that our results showed that the expressions of 17 prognosis-related hub genes were significantly correlated based on Pearson correlation. We here offer a newly genetic biomarker for the prediction of EC patients’ prognosis.
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Molle, Céline, Tong Zhang, Laure Ysebrant de Lendonck, Cyril Gueydan, Mathieu Andrianne, Félicie Sherer, Gaetan Van Simaeys, Perry J. Blackshear, Oberdan Leo, and Stanislas Goriely. "Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease." Journal of Experimental Medicine 210, no. 9 (August 12, 2013): 1675–84. http://dx.doi.org/10.1084/jem.20120707.
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Interleukin (IL) 12 and IL23 are two related heterodimeric cytokines produced by antigen-presenting cells. The balance between these two cytokines plays a crucial role in the control of Th1/Th17 responses and autoimmune inflammation. Most studies focused on their transcriptional regulation. Herein, we explored the role of the adenine and uridine–rich element (ARE)–binding protein tristetraprolin (TTP) in influencing mRNA stability of IL12p35, IL12/23p40, and IL23p19 subunits. LPS-stimulated bone marrow–derived dendritic cells (BMDCs) from TTP−/− mice produced normal levels of IL12/23p40. Production of IL12p70 was modestly increased in these conditions. In contrast, we observed a strong impact of TTP on IL23 production and IL23p19 mRNA stability through several AREs in the 3′ untranslated region. TTP−/− mice spontaneously develop an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. We observed IL23p19 expression within skin lesions associated with exacerbated IL17A and IL22 production by infiltrating γδ T cells and draining lymph node CD4 T cells. We demonstrate that the clinical and immunological parameters associated with TTP deficiency were completely dependent on the IL23–IL17A axis. We conclude that tight control of IL23 mRNA stability by TTP is critical to avoid severe inflammation.
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Lopes, M., F. Traina, J. K. Pereira, P. De Melo Campos, J. A. Machado-Neto, I. Lorand-Metze, S. T. Olalla Saad, and P. Favaro. "P-243 IL32 mRNA levels in peripheral blood CD3+ cells from MDS patients." Leukemia Research 37 (May 2013): S132—S133. http://dx.doi.org/10.1016/s0145-2126(13)70290-x.
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Liu, Jiapei, Kaibo Yang, Hua Jin, and Qifa Liu. "Transcriptomic Profiling of Circulating Extrafollicular Helper T-like Cells in Patients with Active Chronic Graft-Versus-Host Disease Reveals Distinct Apoptosis Resistance." Blood 138, Supplement 1 (November 5, 2021): 4882. http://dx.doi.org/10.1182/blood-2021-148964.
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Abstract In our previous studies, we identified circulating extrafollicular helper T-like cells (CD44 hiCD62L loPSGL-1 loCD4 +, c-extrafollicular Th-like) in human peripheral blood. C-extrafollicular Th-like cells are associated with the development of cGVHD. However, the exact molecular mechanism of these cells in patient with active cGVHD is still unclear. We performed the whole transcriptome analysis of c-extrafollicular Th-like cells from patients with active cGVHD and without cGVHD to explore the molecular mechanism. We identified 4661 differentially expressed genes between two groups by RNA-sequencing. Upregulated expression of Ca2 + influx and protein kinase C signaling pathway induced genes that establish T cell receptor hyper-activation signature were observed in active cGVHD patients. Expression of several inflammation cytokines and receptors were also increased, including IL23, IL27, IL2RA, IL32, IL24 and IL7R. Furthermore, tumor necrosis factor receptor associated factor 1 (TRAF1) and Bcl-2 genes that linked to resist apoptosis were found upregulated. Consistently, we confirmed that the BCL-2 expression of c-extrafollicular helper Th-like cells was significant higher in active cGVHD patients than no cGVHD patients(P=0.02) by quantitative polymerase chain reaction (qPCR). Our study sheds new light on molecular mechanism of the c-extrafollicular Th-like in patient with active cGVHD. Targeting these signaling pathways might blunt the development of cGVHD. Disclosures No relevant conflicts of interest to declare.
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Smolnikova, M. V., A. A. Barilo, M. A. Malinchik, and S. V. Smirnova. "Search for genetic markers of predisposition to psoriasis and psoriatic arthritis." Medical Immunology (Russia) 22, no. 5 (December 1, 2020): 925–32. http://dx.doi.org/10.15789/1563-0625-sfg-2050.
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Psoriasis (PS) and psoriatic arthritis (PsA) are interrelated diseases that occur in approximately 30% of patients and are characterized by the presence of a systemic inflammatory reaction that occurs as a result of a violation of the functional state of the immune system. With the advent of new technologies, several new pro-inflammatory cytokines, such as IL-23, IL-31, and IL-33, which play an important role in the pathogenesis of the psoriatic process, have been discovered and characterized. It was determined that single nucleotide polymorphisms (SNPs) in the promoter regions of the IL23, IL31 and IL33 genes play an important role in controlling the expression of relevant cytokines involved in the immunopathogenesis of psoriatic disease. The purpose of the study: to analyze the distribution of genotypes and allelic variants of polymorphisms of the IL23A (rs2066808), IL23R (rs2201841), IL31 (rs7977932) and IL33 (rs7044343), in order to search for genetic markers of predisposition to psoriasis and psoriatic arthritis. Materials and methods. The genotyping of the patients was conducted: psoriasis (PS, n = 77), median age 31.0 years (27.0-43.0), psoriatic arthritis (PsA, n = 99), median age 49.0 years (39.0-56.0) and practically healthy residents of Krasnoyarsk (n = 103), a median age of 32.0 years (24.0-38.0). DNA was isolated from whole venous blood using a standard sorbent kit. Genotyping of single nucleotide polymorphisms IL23A (rs2066808), IL23R (rs2201841), IL31 (rs7977932), IL33 (rs7044343) was carried out using real-time PCR using specific oligonucleotide primers and fluorescentlylabeled probes. Results and discussion. The frequencies of allelic variants of the studied cytokine genes in the control group obtained during the study correspond to their distribution in Caucasoid populations – the alleles IL23A * T, IL23R * T, IL31 * C, IL33 * C prevail. When comparing the distribution frequency of allelic variants of the IL23A, IL23R, IL31, IL33 genes, we did not obtain statistically significant differences between patients and the control group. Conclusions. Despite the fact that when comparing the distribution frequency of allelic variants of the IL23A, IL23R, IL31, IL33 genes, we did not obtain statistically significant differences between the patients and the control group, there are results worthy of attention. So, in patients with PS, the frequency of the C * IL23A allelic variant (rs2066808) is lower than in the population sample, which may indicate its specific role in relation to the development of the disease. All this dictates the need to continue research with the assessment of other SNPs and increase the sample of patients in search of potential genetic markers of psoriatic disease.
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Powell, Nick, Eirini Pantazi, Polychronis Pavlidis, Anastasia Tsakmaki, Katherine Li, Feifei Yang, Aimee Parker, et al. "Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells." Gut 69, no. 3 (December 2, 2019): 578–90. http://dx.doi.org/10.1136/gutjnl-2019-318483.
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ObjectiveThe functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells.DesignTo investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD.ResultsAs well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn’s disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response.ConclusionsOur data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis.Trial registration numberNCT02749630.
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He, Jianya, Wen Ye, Ni Kou, Kang Chen, Bai Cui, Xiaohong Zhang, Shuhai Hu, Tingjiao Liu, Lan Kang, and Xiaojie Li. "MicroRNA‐29b‐3p suppresses oral squamous cell carcinoma cell migration and invasion via IL32/AKT signalling pathway." Journal of Cellular and Molecular Medicine 24, no. 1 (January 2020): 841–49. http://dx.doi.org/10.1111/jcmm.14794.
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Tokuyama, Michio, and Tomotaka Mabuchi. "New Treatment Addressing the Pathogenesis of Psoriasis." International Journal of Molecular Sciences 21, no. 20 (October 11, 2020): 7488. http://dx.doi.org/10.3390/ijms21207488.
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Psoriasis is an immune cell-mediated inflammatory skin disease. The interleukin (IL)23/IL17 axis plays an important role in the development of psoriasis. The effectiveness of biologic treatments such as tumor necrosis factor (TNF)α inhibitors (infliximab, adalimumab, certolizumab pegol), IL23 inhibitors (ustekinumab, guselkumab, tildrakizumab, risankizumab), and IL17 inhibitors (secukinumab, ixekizumab, brodalumab) have verified these findings. Immune-related cells such as dendritic cells (DCs) and macrophages, in addition to Toll-like receptors and cytokines such as interferon (IFN)α, TNFα, IFNɤ, IL12, IL22, IL23, and IL17, are related to the pathogenesis of psoriasis. Here, we first review new insights regarding the pathogenesis of psoriasis, as it relates to DCs, Langerhans cells, macrophages, the signal transducer and activator of transcription 3 pathway, and aryl hydrocarbon receptor in cutaneous vascular endothelial cells. Based on these findings, we summarize currently available oral treatments and biologics. Furthermore, we describe a new treatment option including Janus kinase inhibitor, tyrosine kinase 2 inhibitor, modulator of sphingosine 1-phosphate receptor 1, and Rho-associated kinase 2 inhibitor.
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Koltsova, Ekaterina, Iuliia Peshkova, Amiran Dzutsev, Turan Aghayaev, Stanley Hazen, Giorgio Trinchieri, and Aliia Fatkhullina. "Cytokine mediated control of microbiota and inflammation in atherosclerosis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 191.12. http://dx.doi.org/10.4049/jimmunol.202.supp.191.12.
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Abstract Atherosclerosis is lipid-driven, chronic inflammatory disease of the arterial wall. While commensal microbiota is involved in the distal regulation of systemic immune responses, how this distant connection influences the development of atherosclerosis and what are the underlying mechanisms remains largely unknown. In a mouse model of atherosclerosis, we found that disease was augmented when expression of the otherwise inflammatory cytokine IL23 was ablated. IL23 and its immediate downstream target IL22 restrict atherosclerosis by preventing outgrowth of microbiota, as inactivation of IL23/IL22 signaling led to dysbiosis and expansion of bacteria with pro-atherogenic properties, due to defective production of antimicrobial peptides in the intestine. These pro-atherogenic bacteria contributed to elevated serum levels of several pro-atherogenic metabolites, which in turn induced osteopontin (OPN) expression by subsets of myeloid cells including aortic macrophages. Microbiota transfer from IL23 deficient mice accelerated atherosclerosis, while microbial depletion or IL22 administration reduced aortic osteopontin expression and ameliorated the disease. Overall, our work uncovers the innate inflammatory IL23-IL22 cytokine signaling axis as a key regulator of atherosclerosis that controls diet-induced expansion of pro-atherogenic microbiota, and argues for informed usage of cytokine blockers with regard to cardiovascular side effects driven by microbiota and inflammation
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Sorrentino, Carlo, Stefania Livia Ciummo, Luigi D'Antonio, Cristiano Fieni, Paola Lanuti, Alice Turdo, Matilde Todaro, and Emma Di Carlo. "Interleukin-30 feeds breast cancer stem cells via CXCL10 and IL23 autocrine loops and shapes immune contexture and host outcome." Journal for ImmunoTherapy of Cancer 9, no. 10 (October 2021): e002966. http://dx.doi.org/10.1136/jitc-2021-002966.
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BackgroundBreast cancer (BC) progression to metastatic disease is the leading cause of death in women worldwide. Metastasis is driven by cancer stem cells (CSCs) and signals from their microenvironment. Interleukin (IL) 30 promotes BC progression, and its expression correlates with disease recurrence and mortality. Whether it acts by regulating BCSCs is unknown and could have significant therapeutic implications.MethodsHuman (h) and murine (m) BCSCs were tested for their production of and response to IL30 by using flow cytometry, confocal microscopy, proliferation and sphere-formation assays, and PCR array. Immunocompetent mice were used to investigate the role of BCSC-derived IL30 on tumor development and host outcome. TCGA PanCancer and Oncomine databases provided gene expression data from 1084 and 75 hBC samples, respectively, and immunostaining unveiled the BCSC microenvironment.ResultshBCSCs constitutively expressed IL30 as a membrane-anchored glycoprotein. Blocking IL30 hindered their proliferation and self-renewal efficiency, which were boosted by IL30 overexpression. IL30 regulation of immunity gene expression in human and murine BCSCs shared a significant induction of IL23 and CXCL10. Both immunoregulatory mediators stimulated BCSC proliferation and self-renewal, while their selective blockade dramatically hindered IL30-dependent BCSC proliferation and mammosphere formation. Orthotopic implantation of IL30-overexpressing mBCSCs, in syngeneic mice, gave rise to poorly differentiated and highly proliferating MYC+KLF4+LAG3+ tumors, which expressed CXCL10 and IL23, and were infiltrated by myeloid-derived cells, Foxp3+ T regulatory cells and NKp46+RORγt+ type 3 innate lymphoid cells, resulting in increased metastasis and reduced survival. In tumor tissues from patients with BC, expression of IL30 overlapped with that of CXCL10 and IL23, and ranked beyond the 95th percentile in a Triple-Negative enriched BC collection from the Oncomine Platform. CIBERSORTx highlighted a defective dendritic cell, CD4+ T and γδ T lymphocyte content and a prominent LAG3 expression in IL30highversus IL30low human BC samples from the TCGA PanCancer collection.ConclusionsConstitutive expression of membrane-bound IL30 regulates BCSC viability by juxtacrine signals and via second-level mediators, mainly CXCL10 and IL23. Their autocrine loops mediate much of the CSC growth factor activity of IL30, while their paracrine effect contributes to IL30 shaping of immune contexture. IL30-related immune subversion, which also emerged from computational analyses, strongly suggests that targeting IL30 can restrain the BCSC compartment and counteract BC progression.
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Ohmatsu, Hanako, Daniel Humme, Nicholas Gulati, Juana Gonzalez, Markus Möbs, Mayte Suárez-Fariñas, Irma Cardinale, et al. "IL32 Is Progressively Expressed in Mycosis Fungoides Independent of Helper T-cell 2 and Helper T-cell 9 Polarization." Cancer Immunology Research 2, no. 9 (June 17, 2014): 890–900. http://dx.doi.org/10.1158/2326-6066.cir-13-0199-t.
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Wen, Siyang, Yixuan Hou, Lixin Fu, Lei Xi, Dan Yang, Maojia Zhao, Yilu Qin, Kexin Sun, Yong Teng, and Manran Liu. "Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell invasion and metastasis via integrin β3–p38 MAPK signalling." Cancer Letters 442 (February 2019): 320–32. http://dx.doi.org/10.1016/j.canlet.2018.10.015.
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Karim, Ahmad Faisal, Anthony R. Soltis, Nadia P. Ewing, Clifton L. Dalgard, Matthew D. Wilkerson, and Kathleen P. Pratt. "Hemophilia A Inhibitor Subjects Show Unique PBMC Gene Expression Profiles That Include up-Regulated Innate Immune Modulators." Blood 134, Supplement_1 (November 13, 2019): 160. http://dx.doi.org/10.1182/blood-2019-124855.
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The formation of pathological anti-FVIII antibodies, referred to as "inhibitors", is the most serious complication of therapeutic FVIII infusions, affecting up to one third of severe Hemophilia A (HA) patients. Intensive FVIII therapy, i.e. "Immune Tolerance Induction" (ITI), enables ~2/3 of treated patients to achieve peripheral tolerance to FVIII. FVIII inhibitor formation is a classical T-cell dependent adaptive immune response. As such, it requires help from the innate immune system. However, the roles of innate immune cells and mechanisms of inhibitor development versus immune tolerance, achieved with or without ITI therapy, are not well understood. To address these questions, we carried out temporal transcriptomics profiling of FVIII-stimulated peripheral blood mononuclear cells (PBMCs) from HA subjects with and without a current or historic inhibitor using RNA-seq. PBMCs were isolated from 40 subjects in the following groups: (A) HA with an inhibitor that resolved either following ITI or spontaneously; (B) HA with a current inhibitor; (C) HA with no inhibitor history and (D) non-HA healthy controls. PBMCs were rested overnight and then stimulated with 5 nM FVIII, and total RNA was isolated 4, 16, 24 and 48 hours following stimulation. RNA from unstimulated cells at t = 4 hrs served as a negative control. Time-series differential expression analysis was performed with DESeq2 and genes with a log likelihood ratio test FDR <0.05 and an absolute fold change >1.25 at at least one stimulation time point compared to control were deemed significant. Subjects with a resolved past inhibitor (Group A) showed differential expression of only 15 genes. In contrast, subjects with a current inhibitor (Group B) showed differential expression of 56 genes. A clustering analysis divided the temporal trajectories of Group B genes into 3 distinct clusters. Twenty-three genes were up-regulated at 16 hr and 21 genes at 48 hr post-stimulation, respectively. Interestingly, gene ontology (GO) enrichment analysis of these genes revealed enrichments for innate immune modulators, including NLRP3, TLR8, IL32, CLEC10A and COLEC12.NLRP3 and TLR8 are associated with enhanced secretion of the pro-inflammatory cytokines IL-1beta and TNF-alpha, while IL32, which has several isoforms, has been associated with both inflammatory and regulatory immune processes. Expression levels of NLRP3, TLR8, CLEC10A and IL32 transcripts were validated by real time PCR, and changes in RNA transcript abundances correlated well with the RNA-seq results. IL-32 results were validated by both RT-qPCR on an aliquot of the original RNA sample and ELISA to measure the cytokine in supernatants at t=48 hrs. HA subjects with no inhibitor history (Group C) had 195 differentially expressed genes whose temporal profiles fell into 4 distinct clusters. GO enrichment analysis revealed biological processes related to epithelial cell proliferation, responses to toxic substances, and positive/negative regulation of cytokine secretion (TNF, NQO1, PMEPA1). The non-HA healthy control subjects (Group D) also showed cellular responses to ex vivo FVIII stimulation. A total of 63 differentially regulated genes fell into 4 distinct clusters. GO analysis identified expression patterns associated with leukocyte-mediated immunity, T-cell activation, and a hypoxia response. Overall, distinct transcriptional signatures were identified for each of the four groups, providing clues as to cellular mechanisms leading to or accompanying their disparate anti-FVIII antibody responses. We are currently characterizing PBMC immune cell subsets, e.g. macrophages and CD4+ T cells, to identify specific cell types responsible for the differentially regulated genes. Cellular responses of tolerized HA subjects and healthy non-HA controls were consistent with the known immunogenicity of FVIII, including persistence of FVIII-specific CD4+ T cells even in individuals with no measurable FVIII inhibitor. The inflammatory status of HA patients suffering from an ongoing inhibitor clearly includes up-regulation of innate immune modulators, some of which may act as ongoing danger signals that influence the responses to, and eventual outcome of, ITI therapy. Disclosures Pratt: Grifols, Inc: Research Funding; Bloodworks NW: Patents & Royalties: inventor on patents related to FVIII immunogenicity.
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Jihene, Ayari, Karrit Sarra, Haj Ammar Shourouk, Bouhlel Mehdi, Balti Mehdi, Zribi Aref, Fendri Sana, et al. "Prognostic Value of Circulating Cytokines in Breast Cancer." Cancer Medicine Journal 3, no. 1 (June 30, 2020): 1–9. http://dx.doi.org/10.46619/cmj.2020.3-1015.
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Objectives: The aim of this study was to measure circulating cytokines (IL17, IL6, IL22, IL23 and TNFα) and to evaluate their role as markers and in prognosis in Tunisian patients with breast cancer. Materials and methods: Our prospective study enrolled 60 untreated patients affected by breast cancer. We evaluated their levels of TNF-α and IL6 within solid-phase, two-site chemoluminescent enzyme immunemetric assay. Seric levels of IL17, IL22 and IL23 were measured by ELISA sandwich technique and results compared by chi-2 square. Results: Our population, all females, have a mean age of 48 years, a localized disease in 75% of cases and metastatic in the resting 25%. The mean cytokines levels for IL6, IL17, TNFα, IL22 and IL23 were respectively 4.8 ± 7.2 pg/ml, 0.27 ± 0.69 pg/ml, 5.9 ± 2.2 pg/ml, 50.8 ± 34.7 pg/ml and 18 ± 30.9 pg/ml. Serum IL6 levels were significantly higher with advanced stages and particularly, metastatic stage IV and in relapsing patients. We observed also higher TNFα levels in advanced stages (III and IV) and IL22 in cases with grade III SBR. For IL23, higher levels were observed in axillary node positive cases and in patients younger than 35 years. IL17 was significantly higher with patients who relapsed. Conclusion: Our results highlight the role of cytokines in the serum as potential prognostic biomarkers in breast cancer patients, which could contribute to tumor growth and progression. Analyzing serum cytokine levels may help to identify patients with poor prognosis who may benefit from more aggressive treatment.
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Rodolfo, M., C. Zilocchi, C. Melani, B. Cappetti, I. Arioli, G. Parmiani, and M. P. Colombo. "Immunotherapy of experimental metastases by vaccination with interleukin gene-transduced adenocarcinoma cells sharing tumor-associated antigens. Comparison between IL-12 and IL-2 gene-transduced tumor cell vaccines." Journal of Immunology 157, no. 12 (December 15, 1996): 5536–42. http://dx.doi.org/10.4049/jimmunol.157.12.5536.
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Abstract We have compared the therapeutic activity and characterized the antitumor response induced by IL-12 and IL-2 gene-transduced tumor cell vaccines. Mice bearing lung metastases of the BALB/c colon carcinoma C51 were treated with syngenic, histologically related, and antigenically cross-reacting irradiated IL-12 (C26/IL12) or IL-2 (C26/IL2) gene-transduced C26 tumor cells given s.c. Vaccination with C26/IL12 cells cured 40% of mice, while vaccination with C26/IL2 cells reduced the number of metastatic nodules without affecting survival. Despite this difference, similar antitumor CTL activation was shown in mice treated with C26/IL12 or C26/IL2 cells. The lytic pattern of CTL was shown to be directed to tumor-associated Ags (TAA) shared between the colon carcinomas C51, C26, and CC36 as well as with other syngenic tumors. Both treatments induced anti-TAA Abs, but only sera from mice treated with C26/IL12 contained Ab that lysed tumor cells in a C-dependent cytotoxicity assay. Early infiltration of activated T cells was found in the lungs of mice vaccinated with C26/IL12. CD4+ lymphocytes purified from the lymph nodes draining the vaccination site or from the spleen showed a higher production of IFN-gamma in response to anti-CD3 mAb in C26/IL12 vaccinated mice, while a higher production of IL-4 was shown in mice vaccinated with C26/IL2 cells. These results indicate that the better therapeutic efficacy of vaccination with C26/IL12 is associated with the production of C-binding Ab, an early infiltration of the metastatic lungs by activated T lymphocytes and a predominant systemic activation of Th1 more than Th2 cells.
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Yoshikawa, Yoshie, Yusuke Sasahara, Katsuyuki Takeuchi, Yoshimasa Tsujimoto, Takashi Hashida-Okado, Yukio Kitano, and Tomoko Hashimoto-Tamaoki. "Transcriptional Analysis of Hair Follicle-Derived Keratinocytes from Donors with Atopic Dermatitis Reveals Enhanced Induction of IL32 Gene by IFN-γ." International Journal of Molecular Sciences 14, no. 2 (February 5, 2013): 3215–27. http://dx.doi.org/10.3390/ijms14023215.
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Bhat, Shreyas, Nilesh Gardi, Sujata Hake, Nirupama Kotian, Sharada Sawant, Sadhana Kannan, Vani Parmar, Sangeeta Desai, Amit Dutt, and Narendra N. Joshi. "Impact of intra-tumoral IL17A and IL32 gene expression on T-cell responses and lymph node status in breast cancer patients." Journal of Cancer Research and Clinical Oncology 143, no. 9 (May 3, 2017): 1745–56. http://dx.doi.org/10.1007/s00432-017-2431-5.
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Javvadi, L. R., V. P. B. Parachuru, T. J. Milne, G. J. Seymour, and Alison M. Rich. "Expression of IL33 and IL35 in oral lichen planus." Archives of Dermatological Research 310, no. 5 (April 9, 2018): 431–41. http://dx.doi.org/10.1007/s00403-018-1829-5.
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Mortezavi, Mahta, and Christopher Ritchlin. "IL12/IL23 Inhibition in the Treatment of Psoriatic Arthritis." Current Treatment Options in Rheumatology 1, no. 2 (April 16, 2015): 197–209. http://dx.doi.org/10.1007/s40674-015-0018-3.
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Gao, Chunji, Xiaohong Li, Jian Ma, Xiaoxiong Wu, Feifei Wang, Meng Li, Li Yu, and Wanming Da. "Ex Vivo Expansion of Highly Purified Human NK Cells.." Blood 114, no. 22 (November 20, 2009): 2157. http://dx.doi.org/10.1182/blood.v114.22.2157.2157.
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Abstract Abstract 2157 Poster Board II-134 Object To optimize the expansion of high purity NK cells from human peripheral blood and explore the changes in biological functions of NK cells after Ex vivo expansion. Methods NK cells were isolated from PBMNC by using miniMACS (Magnetic cell-selection) and NK Cell Isolation Kit II(Miltenyi Biotec, Germany), then they were cultured in SCEM (Stemline Hematopoietic Stem Cell Expansion Medium, Sigma) supplemented with 10% human AB serum and different combinations of interleukin (IL)-2 and/or IL-12, IL-15 for 15 days. Cultures were fed with fresh media and cytokines every 3 days, and were evaluated for cell expansion, phenotype, perforin and granzyme B mRNA expressions, and IFN-γ secretion at the end of the culture period. Results In group IL2+IL15 and IL2+IL15+IL12, cells were expanded 50.46±4.31 and 52.35±6.72 fold, respectively, much more higher than others(P<0.01), but no significant difference between them (P>0.05). And the purity of CD3−CD56+NK cells was over 94% in all groups except the control. The expressions of perforin and granzyme B mRNA of expanded NK cells cultured with cytokines was significantly higher than the starting population(P<0.01), although IL2+IL15+IL12 group was slightly higher than that of IL2+IL15 group, without significant difference (P>0.05). There was great increase in IFN-γ levels in the supernatants of NK cells culture in the presence of cytokines; IL2+IL15+IL12 group and IL2+IL12 group was significantly higher than others(P<0.01). Conclusion High purity NK cells could be efficiently expanded in culture with IL2+IL15, and its biological functions were enhanced in this condition. Disclosures: No relevant conflicts of interest to declare.
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Minaudo, Carla. "Vía JAK-STAT e inhibidores JAK." Dermatología Argentina 28, no. 2 (June 1, 2022): 55–62. http://dx.doi.org/10.47196/da.v28i2.2324.
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La vía JAK-STAT (Janus Kinasas) es una cadena de traducción de señales intracelulares, que se activa a través de receptores de citoquinas I y II. Mediante esta vía, varias moléculas de importancia en dermatología ejercen sus efectos: IL2, IL4, IL7, IL5, IL6, IL9, IL12, IL13, IL15, IL21, IL23, INFa e INFb, entre otras. También es la señal intracelular de hormonas como la prolactina y la hormona de crecimiento. La inhibición de distintos componentes de esta vía es utilizada como terapéutica en enfermedades reumatológicas y un número cada vez mayor de patologías cutáneas. Los inhibidores JAK surgieron en la práctica médica hace aproximadamente 11 años, con el ruxolitinib y poco tiempo después el tofacitinib. En la actualidad, se dispone de varias moléculas aprobadas y muchas otras en etapa experimental. En este artículo se desarrollarán la organización intracelular y las funciones de la vía JAK-STAT con sus variantes principales relacionadas a enfermedades inmunomediadas, así como las características más relevantes de los inhibidores JAK.
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Rodriguez-Nieves, Jennifer, Ryan Tuck, and Kristina De Paris. "JAK/STAT Signaling of Natural Killer (NK) Cells Following Cytokine Stimulation." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 124.20. http://dx.doi.org/10.4049/jimmunol.198.supp.124.20.
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Abstract Natural Killer (NK) cells are an important component of the innate immune system, capable of providing a fast and effective response against virally infected cells. NK cells are mainly characterized by their cytotoxic function and their ability to secrete cytokines. It has been shown that infant NK cells have decreased cytotoxicity and cytokine-secreting function, suggesting hyporesponsiveness of NK cells during the first year of life. Because NK cell activation is dependent on cytokine stimulation, we hypothesized that infant NK cells are hyporesponsive due to deficiencies in signaling following cytokine stimulation. We examined the activation of human infant and adult NK cells in response to IL2, IL12 or IFNα stimulation, cytokines important in NK survival and function. Using Phosflow analysis, we measured the phosphorylation of transcription factors, STATs, specific for the distinct cytokines. Cord blood NK cells showed significantly lower pSTAT activation when compared to adult NK cells when treated with IL2 or IFNα but not IL12. However, despite pSTAT4 activation in response to IL12, no nuclear translocation was observed by ImageStreamX Mark II analysis. NK cells in 6 and 12-month-old infants showed similar frequencies of pSTAT NK cells compared to adults when treated with IL2, IL12 or IFNα, suggesting that cytokine signaling in NK cells is age-dependent. Surprisingly, pSTAT activation was restored in cord blood NK cells when treated with a cocktail of IL2, IL12 and IL15. These results suggest that JAK/STAT signaling in infant NK cells is impaired at different steps in the pathway in response to specific cytokines.
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Saravia, Jordy, Dahui You, John DeVincenzo, and Stephania Cormier. "Group 2 innate lymphoid cells and IL-33 in infant respiratory syncytial virus infection (INC9P.442)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 188.1. http://dx.doi.org/10.4049/jimmunol.192.supp.188.1.
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Abstract Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants with an estimated global impact of 64 million cases and 160,000 deaths each year. Severe RSV infections in infants are characterized by airway obstruction and Th2-biased immune responses, including recruitment of Th2 cells and eosinophils to the lung and elevated Th2 effector cytokines (IL4, IL5, IL13). Early elevations in IL13 following RSV infection of neonatal mice suggest a source other than Th2 cells. Group 2 innate lymphoid cells (ILC2s) are a recently identified population of cells that produce high levels of IL13 and IL5 in response to IL33. There are no data available on the involvement of IL33 or ILC2s in Th2 infant RSV responses. In mice, our data demonstrate that RSV causes rapid IL33 expression and an increase in ILC2 numbers in the lung which are elevated in neonates versus adults. Blocking IL33 in the neonate abrogates this increase in ILC2s while treatment with recombinant IL33 in the adult augments ILC2 levels and increases Th2 cell numbers. In humans, we have observed elevated levels of IL33, IL13, and IL5 in nasal washes from RSV-infected infants. Additionally, ILC2s are present in higher numbers in cord blood mononuclear cells compared to adult peripheral blood mononuclear cells. These data indicate an important role for ILC2s and IL33 in the immunopathogenesis of severe infant RSV infection - for which there remains no adequate therapeutic/vaccine.
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Miguel González, J. A., M. Sánchez Mayor, L. M. Cervera Seco, A. Gaite Reguero, P. Pavlidis, and U. Martínez Marigorta. "P900 Studying causality association of ustekinumab with cardiovascular disease outcomes using Mendelian randomization." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i1013. http://dx.doi.org/10.1093/ecco-jcc/jjac190.1030.
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Abstract Background The human antibody ustekinumab targets the common p40 subunit between both pro-inflammatory interleukin-12 (IL-12) and interleukin-23 (IL-23) that upregulate T cell differentiation towards T helper 1 (TH1) and T helper 17 (TH17) respectively. The blockade of the IL12-IL23 pathway has been shown to be an effective therapeutic option for Inflammatory Bowel Disease treatment, however a recent epidemiological study has reported a potential cardiovascular risk association for ustekinumab treatment in patients at high cardiovascular risk specifically1. We use mendelian randomization (MR) to assess the reliability of this finding. Methods MR uses genetic variation to examine the causal effect of a risk factor (exposure) on a disease (outcome). The basis of MR relies on the use of genetic variants as instrumental variables (IVs) that are reliably related to the risk factor and that are not susceptible of reverse causation and confounding2. We use genetic variants (SNPs) detected in eQTL studies that affect gene expression levels as proxies for the IL12-IL23 pathway genes in order to simulate the biological effect of ustekinumab. A cardiovascular trait-composition composed of different groups of outcomes (acute coronary syndrome, transient ischaemic attack, unstable angina and ischemic stroke) was created to investigate further the possible association of ustekinumab with triggering cardiovascular events. Results Using top cis-eQTLs from the eQTLGen consortium and the Database of Immune Cell Expression (DICE) as IVs for the IL12-IL23 pathway genes, we observed non-significant associations after multiple testing correction for any of the cardiovascular traits. However, we observed a significant positive causal effect for IL12Rβ1 gene in acute coronary syndrome when using IVs from the Genotype-Tissue Expression (GTEx) project. An observation that was also obtained in a meta-analysis specifically for acute coronary syndrome. In addition, we run MR with multiple SNPs associated with IL12-IL23 genes and we did obtain similar results for IL12Rβ1 and acute coronary syndrome. Conclusion Our results suggest that the blockade of the IL12-IL23 pathway with ustekinumab might reduce cardiovascular risk and provide a cardioprotective effect based on the results obtained for acute coronary syndrome. As these results are not in line with previous observational studies1, further investigations are needed to clarify the biological mechanism that may account for these discrepancies. 1. Poizeau et al. JAMA Dermatol (2020). 2. Sanderson et al. Nat Rev (2022).
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Zaharescu, Anamaria, Sorina Mihaela Solomon, Mihaela Gabriela Luca, Vasilica Toma, Ionut Luchian, Irina Georgeta Sufaru, Maria Alexandra Martu, Liliana Foia, and Silvia Martu. "Cuantificarea moleculelor proinflamatorii (IL1-alfa, IL1-beta, IL2, IL 12, IFN-gama, TNF-alfa) in lichid crevicular si ser la pacientii cu leziuni endo-parodontale." Revista de Chimie 70, no. 6 (July 15, 2019): 2252–55. http://dx.doi.org/10.37358/rc.19.6.7316.
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The present research proposes an assessment of the localized inflammatory burden but also at the systemic level by quantitating the pro-inflammatory molecules (IL1-a, IL1-b, IL2, IL12, IFN-g, TNF-a) with endo-periodontal lesions. The study was performed on a group of 146 subjects who, following clinical and radiological examinations, were divided into five groups: healthy endo-periodontal patients, patients with periodontitis, patients with moderate periodontitis, patients with severe periodontitis and patients presenting combined endo-periodontal lesions. IL1-a, IL1-b, IL2, IL12, IFN-g, TNF-a were analysed in crevicular fluid by ELISA and serum by fluorescence flowcytometry. IL1-a and IL1-b showed serum and crevicular fluid values significantly higher than the healthy subjects. Values for IL2, IL12, TNF-a and IFN-g measured in crevicular fluid were higher for groups II, III, IV, and V compared to the group of healthy endo-periodontal subjects. IL2 showed significantly higher serum values for groups III, IV and V than group I. Serum IL12 values were significantly higher than healthy periodontal subjects only for patients with severe periodontitis and endo-periodontal syndrome. Following serum determinations of proinflammatory molecules, patients with endo-periodontal lesions demonstrated significantly higher values even in subjects with severe periodontitis; these data indicate a much higher risk for these patients to develop and maintain systemic maladies, as is the role local inflammation can play over the general inflammatory status of the patient.
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Long, Nguyen Phuoc, Seongoh Park, Nguyen Hoang Anh, Jung Eun Min, Sang Jun Yoon, Hyung Min Kim, Tran Diem Nghi, et al. "Efficacy of Integrating a Novel 16-Gene Biomarker Panel and Intelligence Classifiers for Differential Diagnosis of Rheumatoid Arthritis and Osteoarthritis." Journal of Clinical Medicine 8, no. 1 (January 6, 2019): 50. http://dx.doi.org/10.3390/jcm8010050.
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Introducing novel biomarkers for accurately detecting and differentiating rheumatoid arthritis (RA) and osteoarthritis (OA) using clinical samples is essential. In the current study, we searched for a novel data-driven gene signature of synovial tissues to differentiate RA from OA patients. Fifty-three RA, 41 OA, and 25 normal microarray-based transcriptome samples were utilized. The area under the curve random forests (RF) variable importance measurement was applied to seek the most influential differential genes between RA and OA. Five algorithms including RF, k-nearest neighbors (kNN), support vector machines (SVM), naïve-Bayes, and a tree-based method were employed for the classification. We found a 16-gene signature that could effectively differentiate RA from OA, including TMOD1, POP7, SGCA, KLRD1, ALOX5, RAB22A, ANK3, PTPN3, GZMK, CLU, GZMB, FBXL7, TNFRSF4, IL32, MXRA7, and CD8A. The externally validated accuracy of the RF model was 0.96 (sensitivity = 1.00, specificity = 0.90). Likewise, the accuracy of kNN, SVM, naïve-Bayes, and decision tree was 0.96, 0.96, 0.96, and 0.91, respectively. Functional meta-analysis exhibited the differential pathological processes of RA and OA; suggested promising targets for further mechanistic and therapeutic studies. In conclusion, the proposed genetic signature combined with sophisticated classification methods may improve the diagnosis and management of RA patients.
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Friedlander, Philip Adam, Karl Wassman, Chrisann Kyi, William K. Oh, and Nina Bhardwaj. "Correlation of consistent blood-based gene expression with change in CTLA4 in two large independent clinical studies of patients with advanced melanoma treated with tremelimumab." Journal of Clinical Oncology 35, no. 7_suppl (March 1, 2017): 6. http://dx.doi.org/10.1200/jco.2017.35.7_suppl.6.
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6 Background: We previously reported 16-gene pre- and 8-gene post-treatment response predictive gene signatures in whole blood that were trained in one cohort (N=210) of advanced melanoma patients treated with tremelimumab and validated in an independent test dataset (N=150) for both response and survival.(SITC 2016 Annual Meeting Poster Submission ID: 214348.) Methods: A correlation matrix was calculated for the change between pre- and post-treatment gene expression for all 169 genes in two independent clinical trials. The genes were ranked by their relationship with CTLA4. Comparison was made between the training and test datasets. Reliable biological signals exceeded technical variance of +/- 0.5 fold change. Results: Correlation of the change in gene expression relative to CTLA4 between the 169 genes in two independent datasets was consistent as to fold change and ranking. The literature describes the genes in the Table as playing a role in anti-CTLA4 and PD-1 immunotherapy. We found only ICOS to be predictive of gene response in our 16-gene pre- and 8-gene post-treatment algorithms. Conclusions: Several genes, such as CTLA4, CD28, CXCR3, IL32, FOXP3, CD25, CCR5, and IFNG, are consistently upregulated one to three fold from anti-CTLA4 immunotherapy but are not predictive of response. ClinicalTrials.gov NCT00257205. [Table: see text]
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HogenEsch, Harm, Srikanth Elesela, Syu-Jhe Chien, Kathleen Silva, Vicki Kennedy, and John P. Sundberg. "Role of group 2 innate lymphoid cells (ILC2) in SHARPIN-deficient mice." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 221.15. http://dx.doi.org/10.4049/jimmunol.198.supp.221.15.
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Abstract SHARPIN is a component of the linear ubiquitination assembly complex and a key regulator of NFkB and integrin signaling. SHARPIN-deficient mice develop a phenotype known as chronic proliferative dermatitis (cpdm), characterized by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. We recently reported that the cutaneous inflammation in SHARPIN-deficient mice (Sharpincpdm) develops independently of B and T lymphocytes. We therefore sought to determine the role of innate lymphoid cells (ILCs) in the dermatitis of Sharpincpdm mice. ILCs were identified as a discrete population of CD45+ Lin−CD90.2hi cells in the skin and draining lymph nodes (LN) of wild type (WT) and Sharpincpdm mice. The number of ILCs was markedly increased in Sharpincpdm mice. The majority of cells were group 2 ILC (ILC2) as indicated by labeling for GATA3, IL5, and IL13. The skin of Sharpincpdm mice had increased expression of Il33 and Tslp mRNA. To determine the role of IL33, double mutant mice were generated in which the receptor for IL33 (Il1lr1 also known as ST2) was deleted. Loss of IL33-signaling greatly reduced the number of ILCs and reduced the severity of the dermatitis. These experiments suggest that the dermatitis in Sharpincpdm mice is driven by IL33-dependent ILC2. Supported by the NIH (AR049288).
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Gang, Spencer S., Michelle L. Castelletto, Emily Yang, Felicitas Ruiz, Taylor M. Brown, Astra S. Bryant, Warwick N. Grant, and Elissa A. Hallem. "Chemosensory mechanisms of host seeking and infectivity in skin-penetrating nematodes." Proceedings of the National Academy of Sciences 117, no. 30 (July 10, 2020): 17913–23. http://dx.doi.org/10.1073/pnas.1909710117.
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Approximately 800 million people worldwide are infected with one or more species of skin-penetrating nematodes. These parasites persist in the environment as developmentally arrested third-stage infective larvae (iL3s) that navigate toward host-emitted cues, contact host skin, and penetrate the skin. iL3s then reinitiate development inside the host in response to sensory cues, a process called activation. Here, we investigate how chemosensation drives host seeking and activation in skin-penetrating nematodes. We show that the olfactory preferences of iL3s are categorically different from those of free-living adults, which may restrict host seeking to iL3s. The human-parasitic threadwormStrongyloides stercoralisand hookwormAncylostoma ceylanicumhave highly dissimilar olfactory preferences, suggesting that these two species may use distinct strategies to target humans. CRISPR/Cas9-mediated mutagenesis of theS. stercoralis tax-4gene abolishes iL3 attraction to a host-emitted odorant and prevents activation. Our results suggest an important role for chemosensation in iL3 host seeking and infectivity and provide insight into the molecular mechanisms that underlie these processes.
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Dibra, Denada, Jeffry Cutrera, Xueqing Xia, and Shulin Li. "IL30—a novel anti-inflammatory cytokine candidate for preventing and treating inflammatory cytokine-induced liver injury in mice. (117.21)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 117.21. http://dx.doi.org/10.4049/jimmunol.186.supp.117.21.
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Abstract The liver is subjected to the lifetime attacks from chronic viral infection, uptake of the therapeutic drugs, life behavior (alcoholic), and environmental contaminants, results in chronic inflammation and fibrosis. It is urgent to discover effective therapeutic agents for preventing and treating livery injury and the ideal drug will be naturally occurring biological inhibitors. Here, we show that IL30 is a potent anti-inflammatory cytokine that inhibits liver toxicity. IL27, which contains IL30 subunit, does not have such a property. Interestingly, IL30 is induced by pro-inflammatory cytokines such as IFNγ. Administration of IL30 via a gene therapy approach prevents and treats both IL12- and IFNγ-induced liver toxicity. These novel observations shed the light on a novel role of IL30 as a therapeutic cytokine that suppresses pro-inflammatory cytokine-associated liver toxicity.
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Sonder, Soren Ulrik, Matthew Plassmeyer, and Oral Alpan. "Novel IL12Rβ1 mutation impairs Th1 response in heterozygote patient." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 196.5. http://dx.doi.org/10.4049/jimmunol.196.supp.196.5.
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Abstract The interleukin-12 Receptor beta-1 chain (12Rβ1) is a subunit in the functional IL12 and IL23 receptor that binds the IL12 p40 subunit of the IL12 and IL23 heterodimers. Patients that are homozygote for “lack of function” mutations in IL12Rβ1 are mainly characterized by defects in the Th1 response resulting in recurrent and severe disease caused by infections with poorly pathogenic mycobacteria and salmonellae. Family members that are heterozygote for these mutations are clinically unaffected. Here we describe a case of a 62 year old female patient that is heterozygote for the novel 12Rβ1 mutation Q238E located in the cytokine binding region. The patient has recurrent infections, poor wound healing, osteomyelitis and persistently positive PPD. Lymphocyte count in the lower end of the normal range. Using flow cytometry analysis of whole blood we showed above normal percentages of NK cells and below normal percentages of T-cells. The patients Th1 response was studied by stimulating PBMC from the patient and healthy controls with IL12 and measuring IFNγ in multiple cell types using flow cytometry. The surface expression of IL12Rβ1 does not differ between the patient and controls; however the results demonstrated a reduction in IFNγ producing CD4+ and CD4+/CD45RO+ cells in the patient compared to the controls. Functional screening for IL12 response may provide a powerful tool in evaluating other patients with recurring infections resulting in more accurate diagnose and efficient treatment.
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Borradaile, Nica M., and J. Geoffrey Pickering. "Polyploidy impairs human aortic endothelial cell function and is prevented by nicotinamide phosphoribosyltransferase." American Journal of Physiology-Cell Physiology 298, no. 1 (January 2010): C66—C74. http://dx.doi.org/10.1152/ajpcell.00357.2009.
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Polyploid endothelial cells are found in aged and atherosclerotic arteries. However, whether increased chromosome content has an impact on endothelial cell function is unknown. We show here that human aortic endothelial cells become tetraploid as they approach replicative senescence. Furthermore, accumulation of tetraploid endothelial cells was accelerated during growth in high glucose. Interestingly, induction of polyploidy was completely prevented by modest overexpression of the NAD+ regenerating enzyme, nicotinamide phosphoribosyltransferase (Nampt). To determine the impact of polyploidy on endothelial cell function, independent of replicative senescence, we induced tetraploidy using the spindle poison, nocodazole. Global gene expression analyses of tetraploid endothelial cells revealed a dysfunctional phenotype characterized by a cell cycle arrest profile (decreased CCNE2/A2, RBL1, BUB1B; increased CDKN1A) and increased expression of genes involved in inflammation ( IL32, TNFRSF21/10C, PTGS1) and extracellular matrix remodeling ( COL5A1, FN1, MMP10/14). The protection from polyploidy conferred by Nampt was not associated with enhanced poly(ADP-ribose) polymerase-1 or sirtuin (SIRT) 2 activity, but with increased SIRT1 activity, which reduced cellular reactive oxygen species and the associated oxidative stress stimulus for the induction of polyploidy. We conclude that human aortic endothelial cells are prone to chromosome duplication that, in and of itself, can induce characteristics of endothelial dysfunction. Moreover, the emergence of polyploid endothelial cells during replicative aging and glucose overload can be prevented by optimizing the Nampt-SIRT1 axis.
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Sinitsky, M. Yu, A. V. Tsepokina, M. A. Asanov, Ya V. Kazachek, A. V. Evtushenko, and A. V. Ponasenko. "The expression level of cytokine genes in the cases of native heart valves in infectious endocarditis." Biomeditsinskaya Khimiya 66, no. 5 (2020): 406–10. http://dx.doi.org/10.18097/pbmc20206605406.
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The expression level of IL1B, IL6, IL8, IL10, IL12A, IL12B, IL18, IL23, IL33, CCL2, and IL1RL1 has been investigated using biopsies of native mitral, aortic, and tricuspid valves obtained during surgical correction of acquired defect from 25 patients with infectious endocarditis. Biopsies of native mitral and aortic valve cusps from 12 patients who underwent surgical correction of acquired heart disease of non-infectious etiology were used as control. We used quantitative PCR with fluorescent dye SYBR Green for determination of the cytokine gene expression level. This study revealed that genes could be subdivided into three groups: (i) genes with increased expression (IL1B, IL6, and IL8); (ii) genes with reduced expression (IL33 and IL1RL1); (iii) genes with unchanged expression (IL12A, IL18, IL23, and CCL2). The IL8 gene expression was characterized by the most pronounced increase (9.83 times versus control), while the IL1RL1 gene demonstrated the most pronounced decrease in its expression (4.17 times). Expression of IL10 and IL12B genes was negligible in all samples.
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Xia, Fei, Zhilong Yu, Aijun Deng, and Guohong Gao. "Identification of molecular subtyping system and four-gene prognostic signature with immune-related genes for uveal melanoma." Experimental Biology and Medicine 247, no. 3 (November 7, 2021): 246–62. http://dx.doi.org/10.1177/15353702211053801.
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Immunotherapy is the most promising treatment for uveal melanoma patients with metastasis. Tumor microenvironment plays an essential role in tumor progression and greatly affects the efficacy of immunotherapy. This research constructed an immune-related subtyping system and discovered immune prognostic genes to further understand the immune mechanism in uveal melanoma. Immune-related genes were determined from literature. Gene expression profiles of uveal melanoma were clustered using consensus clustering based on immune-related genes. Subtypes were further divided by applying immune landscape, and weighted correlation network analysis was performed to construct immune gene modules. Univariate Cox regression analysis was conducted to generate a prognostic model. Enriched immune cells were determined after gene set enrichment analysis. Three major immune subtypes (IS1, IS2, and IS3) were identified, and IS2 could be further divided into IS2A and IS2B. The subtypes were closely associated with uveal melanoma prognosis. IS3 group had the most favorable prognosis and was sensitive to PD-1 inhibitor. Immune genes in IS1 group showed an overall higher expression than IS3 group. Six immune gene modules were identified, and the enrichment score of immune genes varied within immune subtypes. Four immune prognostic genes ( IL32, IRF1, SNX20, and VAV1) were found to be closely related to survival. This novel immune subtyping system and immune landscape provide a new understanding of immunotherapy in uveal melanoma. The four prognostic genes can predict prognosis of uveal melanoma patients and contribute to new development of targeted drugs.
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Chen, Hualin, Wenjie Yang, Xiaoqiang Xue, Yingjie Li, Zhaoheng Jin, and Zhigang Ji. "Integrated Analysis Revealed an Inflammatory Cancer-Associated Fibroblast-Based Subtypes with Promising Implications in Predicting the Prognosis and Immunotherapeutic Response of Bladder Cancer Patients." International Journal of Molecular Sciences 23, no. 24 (December 15, 2022): 15970. http://dx.doi.org/10.3390/ijms232415970.
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Inflammatory cancer-associated fibroblasts (iCAFs) are closely related to progression, anticancer therapeutic resistance, and poor prognosis of bladder cancer (BCa). However, the functional role of iCAFs in BCa has been poorly studied. In our study, two BCa scRNA-seq datasets (GSE130001 and GSE146137) were obtained and integrated by the Seurat pipeline. Based on reported markers (COL1A1 and PDGFRA), iCAFs were identified and the related signature of 278 markers was developed. Following unsupervised consensus clustering, two molecular subtypes of TCGA-BLCA were identified and characterized by distinct dysregulated cancer hallmarks, immunological tumor microenvironments, prognoses, responses to chemotherapy/immunotherapy, and stemness. Subsequently, the robustness of the signature-based clustering, in terms of prognosis and therapeutic response prediction, was validated in a GEO-meta cohort with seven independent GEO datasets of 519 BCa patients, and three immune checkpoint inhibitor (ICI)-treated cohorts. Considering the heterogeneity, re-clustering of iCAFs was performed and a subpopulation, named “LOXL2+ iCAFs”, was identified. Co-culture CM derived from LOXL2 overexpression/silencing CAFs with T24 cells revealed that overexpression of LOXL2 in CAFs promoted while silencing LOXL2 inhibited the proliferation, migration, and invasion of T24 cells through IL32. Moreover, the positive correlation between LOXL2 and CD206, an M2 macrophage polarization marker, has been observed and validated. Collectively, integrated single-cell and bulk RNA sequencing analyses revealed an iCAF-related signature that can predict prognosis and response to immunotherapy for BCa. Additionally, the hub gene LOXL2 may serve as a promising target for BCa treatment.
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Ma, Shuwei, and Yi Qiao. "Molecular mechanism of IL17A-IL17F involved in children with allergic rhinitis through IL17RC-IL33-NF-kB signaling axis." Materials Express 12, no. 5 (May 1, 2022): 668–74. http://dx.doi.org/10.1166/mex.2022.2200.
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Objective: Allergic rhinitis (AR) is a common chronic nasal mucosal congestion disease of children, and its pathogenesis is associated with immune factors. Methods: 50 cases of children were collected and their nasal mucus was used to detect inflammatory factors IL-17A, IL-17F and IL-33 level, as well as the proportion of ILC2 and Th2 in blood labeled by flow cytometry. In addition, the allergic rhinitis model of immature mice was established. HE staining was used to observe nasal mucosa. IgE, IL-17A, IL-17F and IL-33 levels were detected, and the ratio of ILC2 and Th2 in blood was marked by flow cytometry. The expressions of IL17-RC, TRAF6, NF-kBp65 and MAPK protein in IL17RC-IL33-NF-kB signal pathway were measured by western blot. Results: The results indicated that IL-17A, IL-17F and IL-33 were significantly higher in children with allergic rhinitis and young model mice than that in control group. The content of CD4+IL-4+subgroup in Th2 in blood of model mice was high. The same trend as CD127+CD117+CRTH2+subgroup in ILC2. HE staining showed that the nasal mucosa of mice was intact in the control group, but the nasal mucosa epithelium of mice in the model group was destroyed. Conclusion: IL17-RC, TRAF6, NF-kBp65 and MAPK in nasal mucosal of model mice showed high expression, confirming that inflammatory factor IL17A-IL17F activated IL33 transcription through IL17RC and Activated ILC2 and Th2 cells involving in allergic inflammatory responses.
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Chen, Suning, Bjoern Schneider, Stefan Nagel, Robert Geffers, Maren Kaufmann, Hilmar Quentmeier, Hans G. Drexler, and Roderick A. F. MacLeod. "Spliceosomal Targeting in Acute Myeloid Leukemia Cells with ETV6-NTRK3 Fusion." Blood 114, no. 22 (November 20, 2009): 5042. http://dx.doi.org/10.1182/blood.v114.22.5042.5042.
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Abstract Abstract 5042 Background In acute myeloid leukemia (AML) a recurrent chromosome abnormality t(12;15)(p13;q25) fuses ETV6 with NTRK3. This rearrangement uniquely occurs in both solid tumors – including secretory breast cancer where it has been recently shown to target WNT signalling (Li et al., Cancer Cell 2007, 12: 542) - and leukemia, but has yet to be characterized in the hematologic setting. Tyrosine receptor kinases (TRK) play key roles in leukemogenesis and already serve as therapeutic targets. We set out to characterize potential downstream targets of ETV6-NTKR3 in AML cells. Methods and Cells By applying molecular cytogenetics, rapid amplification of c-DNA ends, microarray transcriptional profiling, reverse transcriptase quantitative-PCR, sequencing technology, and pathway analysis we defined and characterized the transcriptosome of a t(12;15) cell line (AP-1060) recently established from a patient with acute promyelocytic leukemia. We also investigated the transcriptional responses of AP-1060 cells to TRKi(nhibitor). For comparison we used, firstly a panel of 12 AML cell lines lacking ETV6-NTRK3 or PML-RARA, followed by NB-4 cells with solo PML-RARA. Results FISH confirmed ETV6 rearrangement, while 3′-RACE and RT-PCR identified and confirmed ETV6-NTRK3 fusion transcripts. Sequencing revealed both ETV6 exon-4 / NTKR3 exon-14, and ETV6 exon-2 / exon-18 of NTKR3 (hematopoietic) transcripts - the former dominating. Comparative transcriptional profiling of AP-1060 and control AML cells with or without PML-RARA showed upregulation of RAS-MAPK and PI3K-AKT related genes, highlighting the involvement of both TRK physiological signaling pathways via ETV6-NTRK3. Top genes upregulated in AP-1060 confer signatures both for AML - CCNA1, CD96, DSU, EVI1, HGF, IL32, LGALS3, MDS1, TLE1, TSPAN2; and lymphocyte development - BSPRY, BST1, CCR6, EMP1, GIMAP1, GZMA, PLEKHG1. Several primitive hematopoietic or stem cell mRNAs were also overexpressed, including PRSS2, CD96, SIPA1L2, and PYHIN1. Prominent downregulated genes also included: ADD3, CD36, HOXA-9/10, LGALS9, MALAT1, PGDS, PLA2G4A (AML signature); HOXB4, KIAA1949, NR2F6, TEAD4 (stem cell); and LY6E, TRIM44 (lymphocyte signature). Growth and proliferation of ETV6-NTKR3 cells was exquisitely sensitive to TRKi treatments which spared control AML and to which NB-4 cells were highly resistant. Accordingly we used pharmacologic modulation of conspicuously expressed genes by small molecule TRKi treatment to highlight likely kinase signaling targets among conspicuously expressed genes. Several candidate target genes thus emerged, notably AWNT1, IL32, and the MDS-EVI1 fusion transcript. Salient pharmacologically unmodulated genes were preferentially stem cell in character highlighting this setting for t(12;15) formation in AP-1060 cells. Bioinformatic pathway analysis (http://david.abcc.ncifcrf.gov/) of both up- and down- conspicuously regulated genes identified “Alternative Splicing” as top category, with respectively 743 and 373 alternate spliceform genes up- and down-regulated. These included several genes whose spliceforms may be differentially expressed in oncogenesis, including MDS1-EVI1/EVI1, MALAT1, and WT1/AWT1. Interestingly, a key pre-mRNA splicing gene, MBNL2 was conspicuously downregulated, while another spliceosomal component THOC5 (C22orf19), recently identified as a leukemic kinase signalling target (Pierce et al., Br J Haematol 2008;141:641), is upregulated. Conclusions We present a human leukemia model and resource for ETV6-NTRK3. Taken together, our findings support spliceosomal targeting by ETV6-NTRK3 and suggest a possible underlying mechanistic framework. Additional targets, e.g. WNT signaling, seem to be shared with solid tumors bearing the same oncogene fusion. Perspectives: Future work includes transcriptosomal analysis of AP-1060 cells after knockdown of ETV6-NTRK3 and key splicesomal genes, such as THOC5, by short-hairpin RNAs, and novel, highly selective 4-aminopyrazolylpyrimidine TRKi (Thress et al., Mol Cancer Therapy 2009;8:1818). Disclosures No relevant conflicts of interest to declare.
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Yano, Hiroshi, Deepali V. Sawant, Mengting Liao, Tullia Bruno, Maria Chikina, Creg J. Workman, and Dario AA Vignali. "Inhibitory cytokines mark distinct subpopulations of intratumoral regulatory T cells." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 155.7. http://dx.doi.org/10.4049/jimmunol.198.supp.155.7.
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Abstract Regulatory T cells (Tregs) play a crucial role in the maintenance of self-tolerance and the resolution of inflammation; however, they also negatively regulate anti-tumor immunity by contributing to the immunosuppressive tumor microenvironment. Our previous studies have shown that the inhibitory cytokine interleukin-35 (IL35), a member of the IL12 cytokine family, is preferentially expressed by activated Tregs and the IL35 expression is required for the maximum suppressive activity of Tregs. To investigate the role of Treg-derived IL35 in the tumor microenvironment, we generated a Treg-specific IL35 reporter knockin mouse as well as a Treg-specific IL35 deletion mouse. We demonstrated that IL-35+ Tregs are preferentially enriched in the B16 melanoma tumor microenvironment and actively involved in tumorigenesis by promoting the expression of multiple inhibitory receptors in CD8+ tumor-infiltrating T lymphocytes (TILs). However, the impact of IL35 relative to IL10 and the phenotype of IL35+ Tregs relative to other Treg subpopulations in the tumor microenvironment have not been fully elucidated. We have assessed the expression of IL35 and IL10 in intratumoral Tregs and the phenotype and function of cytokine producing subpopulations using a triple Foxp3/Ebi3/Il10 reporter knockin mouse. We have also assessed IL35/IL10 expression in Tregs infiltrating several human tumors. Interestingly, there are distinct IL35-/IL10-expressing Treg subpopulations in mouse and human tumors. We continue to characterize the phenotype and function of intratumoral Treg subpopulations in mouse and human tumors.
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Fogel, O., E. Rivière, R. Seror, G. Nocturne, B. Ly, S. Boudaoud, J. E. Gottenberg, et al. "AB0150 Understanding The Role of The IL12/iL35 Balance in Sjögren Syndrome." Annals of the Rheumatic Diseases 75, Suppl 2 (June 2016): 948.1–948. http://dx.doi.org/10.1136/annrheumdis-2016-eular.5756.
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mathur, Ramkumar, Yuan Liao, Xiaofeng Zhao, Yunfei Huang, and Xinjun Zhu. "IL23/MTOR Axis in CX3CR1 Residential Macrophages Modulates IL22-Mediated Intestinal Fibrosis." Gastroenterology 152, no. 5 (April 2017): S612. http://dx.doi.org/10.1016/s0016-5085(17)32176-5.
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Ayari, Jihene Braham, Shourouk Haj Ammar, Mehdi Balti, Mouna Ben Azaiz, Aref Zribi, Sana Fendri, Sonia Ben Nasr, et al. "Prognostic value of circulating cytokines in breast cancer: A prospective study in sixty breast cancer patients in Tunisia." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e12592-e12592. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e12592.
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e12592 Background: Breast cancer is the second most common cancer and the fifth most common cause of cancer mortality worldwide. The functional relationship between inflammation and cancer is an old concept of cancero- genesis, and it is now clear that inflammatory process certainly potentiates and/or promotes neoplastic risk. However, many of the molecular and cellular mechanisms mediating this relationship remain unresolved. The aim of this study is to measure the level of circulating cytokines (IL17, IL6, IL22, IL23 and TNFα) in breast cancer patients in Tunisia, and to evaluate their implication as prognostic factors. Methods: Serum samples were collected prospectively from sixty breast cancer patients in Tunisia. TNF-α and IL6 levels were determined using the technique of a solid-phase, two-site chemo-luminescent enzyme immune-metric assay (Immulite 1000, USA). Serum levels of IL17, IL22 and IL23 were measured by enzyme-linked immunosorbent assays (ELISA) sandwich method. Results: The mean age of patients is 48 years, and fourth of them were metastatic. The mean level of cytokines IL6, IL17, TNFα, IL22 and IL23 were respectively 4.80 ± 7.26 pg/ ml (min 2, max 36.80 pg/ ml), 0.27 ± 0.69 pg/ ml (min 0, max 3.62 pg/ ml), 5.93 ± 2.27 pg/ ml (min 4, max 15.30 pg/ml), 50.82 ± 34.78 p/ml (min 26.48, max 199.48 pg/ ml) and 18.05 ± 30.91 pg/ ml (min 0, max 200.21 pg/ml). Serum IL6 level was significantly higher in advanced stages (p = 0.013), especially in metastatic cases (p = 0.001) and in patients who had recurrent disease (p = 0.010). High level of TNFα was also significantly associated with advanced stage (stage III and IV) (p = 0.019), and high level of IL22 was significantly associated with a high histopathological grade (Grade III of Bloom-Richardson grade (SBR)) (p = 0.028). IL23 was found to be significantly increased in lymph node metastatic cases (p = 0.042) and in young patients < 35 years (p = 0.034). Finally, the level of IL17 was significantly higher in patients who had recurrent disease (p = 0.018). Conclusions: Our results highlight the role of certain circulating cytokines as potential prognostic biomarkers in breast cancer patients. The serum analysis of these cytokines, which could contribute to tumor growth and progression, may help to identify groups of patients with poor prognosis and who may need more aggressive treatment. This correlation needs to be evaluated in large prospective validating trials and suggests a rational for the development and use of cytokine blockade in treatment of some groups of breast cancer patients.