Interferon Regulatory Factor 4 (IRF4) is a Prognostic Marker and Related to Immune Infiltration in Breast and Colorectal Cancers

2020 ◽  
Author(s):  
Qingyan Huang ◽  
Zhikang Yu ◽  
Yuhong Gan ◽  
Heming Wu ◽  
Zhixiong Zhong
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Enrichment Analysis ◽  
Interferon Regulatory Factor ◽  
Colorectal Cancers ◽  
Regulatory Factor ◽  
Expression Levels ◽  
Immune Infiltration ◽  
Prognostic Outcome ◽  
Interferon Regulatory Factor 4

Abstract Background: Interferon regulatory factor 4 (IRF4) is a transcription factor that involves in immune cells differentiation. However, it is not clear the relationship between IRF4 and tumor prognosis and immune infiltration.Methods: IRF4 expression levels in different cancers and corresponding normal tissues were analyzed by Oncomine database and Tumor Immune Estimation Resource (TIMER). The prognosis value of IRF4 was assessed by PrognoScan and Kaplan-Meier plotter. The correlation between IRF4 and tumor-infiltrating immune cells and immune cells markers was performed by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). In addition, we explored the genes regulated by IRF4 in Gene Transcription Regulation Database (GTRD) and then put the above genes in Enrich online tool for Gene Ontology (GO) and pathway enrichment analysis.Results: Decreased expression levels of IRF4 were observed in breast and colorectal cancers. Survival analysis shown that high level of IRF4 was associated with better prognostic outcome in breast and colorectal cancer patients. IRF4 expression was positively correlated with infiltrating levels of B cells, CD8+ T cells, T cells (general), dendritic cells (DCs), Th1, T cell exhaustion and monocytes, and immune cells markers. Beside, functional enrichment analysis of the potential genes regulated by IRF4 indicated that IRF4 may be involved in many important biological processes including immune regulation by regulating various genes.Conclusions: High expression of IRF4 shown better prognostic outcome for breast and colorectal cancers. IRF4 was associated with immune infiltration in breast and colorectal cancers. Therefore, IRF4 maybe serve as a potential prognostic biomarker in breast and colorectal cancers with immune infiltration.

scholarly journals Prostaglandin E2 Suppresses Antifungal Immunity by Inhibiting Interferon Regulatory Factor 4 Function and Interleukin-17 Expression in T Cells

Immunity ◽  
2012 ◽  
Vol 36 (4) ◽  
pp. 668-679 ◽  
Author(s):  
Patricia A. Valdez ◽  
Paul J. Vithayathil ◽  
Brian M. Janelsins ◽  
Arthur L. Shaffer ◽  
Peter R. Williamson ◽  
...  
Keyword(s):  
T Cells ◽  
Prostaglandin E2 ◽  
Interferon Regulatory Factor ◽  
Interleukin 17 ◽  
Regulatory Factor ◽  
Antifungal Immunity ◽  
Interferon Regulatory Factor 4

scholarly journals Modulation of T Cell Cytokine Production by Interferon Regulatory Factor-4

2002 ◽  
Vol 277 (51) ◽  
pp. 49238-49246 ◽  
Author(s):  
Chuan-Min Hu ◽  
So Young Jang ◽  
Jessica C. Fanzo ◽  
Alessandra B. Pernis
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Interferon Regulatory Factor ◽  
Luciferase Reporter ◽  
Regulatory Factor ◽  
A Site ◽  
Interferon Regulatory Factor 4 ◽  
Cell Cytokine Production

Production of cytokines is one of the major mechanisms employed by CD4+T cells to coordinate immune responses. Although the molecular mechanisms controlling T cell cytokine production have been extensively studied, the factors that endow T cells with their ability to produce unique sets of cytokines have not been fully characterized. Interferon regulatory factor (IRF)-4 is a lymphoid-restricted member of the interferon regulatory factor family of transcriptional regulators, whose deficiency leads to a profound impairment in the ability of mature CD4+T cells to produce cytokines. In these studies, we have investigated the mechanisms employed by IRF-4 to control cytokine synthesis. We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13. Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter. A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1. These studies thus support the notion that IRF-4 represents one of the lymphoid-specific components that control the ability of T lymphocytes to produce a distinctive array of cytokines.

scholarly journals Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell-Extrinsic Manner

2021 ◽  
Vol 11 ◽  
Author(s):  
Vera Buchele ◽  
Patrick Konein ◽  
Tina Vogler ◽  
Timo Kunert ◽  
Karin Enderle ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Th17 Cell ◽  
Interferon Regulatory Factor ◽  
T Cell Subsets ◽  
Regulatory Factor ◽  
Th17 Response ◽  
Immune Mediated ◽  
Interferon Regulatory Factor 4

Inflammatory bowel diseases (IBDs) are characterized by chronic, inflammatory gastrointestinal lesions and often require life-long treatment with immunosuppressants and repetitive surgical interventions. Despite progress in respect to the characterization of molecular mechanisms e.g. exerted by TNF-alpha, currently clinically approved therapeutics fail to provide long-term disease control for most patients. The transcription factor interferon regulatory factor 4 (IRF4) has been shown to play important developmental as well as functional roles within multiple immune cells. In the context of colitis, a T cell-intrinsic role of IRF4 in driving immune-mediated gut pathology is established. Here, we conversely addressed the impact of IRF4 inactivation in non-T cells on T cell driven colitis in vivo. Employing the CD4+CD25− naïve T cell transfer model, we found that T cells fail to elicit colitis in IRF4-deficient compared to IRF4-proficient Rag1−/− mice. Reduced colitis activity in the absence of IRF4 was accompanied by hampered T cell expansion both within the mesenteric lymph node (MLN) and colonic lamina propria (cLP). Furthermore, the influx of various myeloids, presumably inflammation-promoting cells was abrogated overall leading to a less disrupted intestinal barrier. Mechanistically, gene profiling experiments revealed a Th17 response dominated molecular expression signature in colon tissues of IRF4-proficient, colitic Rag1−/− but not in colitis-protected Rag1−/−Irf4−/− mice. Colitis mitigation in Rag1−/−Irf4−/− T cell recipients resulted in reduced frequencies and absolute numbers of IL-17a-producing T cell subsets in MLN and cLP possibly due to a regulation of conventional dendritic cell subset 2 (cDC2) known to impact Th17 differentiation. Together, extending the T cell-intrinsic role for IRF4 in the context of Th17 cell driven colitis, the provided data demonstrate a Th17-inducing and thereby colitis-promoting role of IRF4 through a T cell-extrinsic mechanism highlighting IRF4 as a putative molecular master switch among transcriptional regulators driving immune-mediated intestinal inflammation through both T cell-intrinsic and T cell-extrinsic mechanisms. Future studies need to further dissect IRF4 controlled pathways within distinct IRF4-expressing myeloid cell types, especially cDC2s, to elucidate the precise mechanisms accounting for hampered Th17 formation and, according to our data, the predominant mechanism of colitis protection in Rag1−/−Irf4−/− T cell receiving mice.

Responsiveness Of Cytogenetically Discrete Human Myeloma Cell Lines To Lenalidomide: Lack Of Correlation With Cereblon and Interferon Regulatory Factor 4 Expression Levels

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1962-1962
Author(s):  
Alexandra J Greenberg ◽  
Denise K Walters ◽  
Bonnie Kaye Arendt ◽  
Renee C. Tschumper ◽  
Shaji K. Kumar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Interferon Regulatory Factor ◽  
Bone Marrow Microenvironment ◽  
Regulatory Factor ◽  
Expression Levels ◽  
Interferon Regulatory Factor 4 ◽  
The Relationship ◽  
Human Myeloma Cell

Abstract The introduction of novel immunomodulatory drugs (IMiDs), such as lenalidomide, has drastically improved the survival of patients with multiple myeloma (MM). While it has been shown that patients with specific cytogenetic subtypes, namely t(4;14), have the best outcomes when treated with bortezomib-based regimens, the relationship between cytogenetic subtypes and response to IMiDs remains unclear. Using DNA synthesis and apoptosis assays, we investigated the relationship between cytogenetic subtype and lenalidomide response in a representative panel of human myeloma cell lines (HMCLs). Additionally, we examined HMCL protein expression levels of the lenalidomide target cereblon (CRBN) and its putative downstream target interferon regulatory factor 4 (IRF4), both of which have previously been shown to be predictive of lenalidomide response in HMCLs. Our results reveal that response to lenalidomide did not correlate with specific cytogenetic translocations. There were, however, distinct groups of lenalidomide-responsive and non-responsive HMCLs, as defined by inhibition of cellular proliferation; notably, all of the hyperdiploid HMCLs fell into the latter category. Repeated dosing of lenalidomide significantly lowered the IC50 of the responsive HMCL ALMC-1 (IC50 = 2.6 μM versus 0.005 μM, p=0.004), but did not have an effect on the IC50 of the non-responsive HMCL DP-6 (p>0.05). Moreover, no association was found between lenalidomide responsiveness and CRBN or IRF4 expression levels. In summary, our data indicate that lenalidomide sensitivity is independent of cytogenetic subtype in HMCLs. Additionally, while CRBN and IRF-4 have been shown to be associated with response to lenalidomide in patients, these findings do not translate back to HMCLs, which could be attributable to factors present in the bone marrow microenvironment. These results suggest that the development of a new treatment paradigm based on cytogenetic subtype of MM alone may be insufficient, and that additional markers may need to be incorporated. Furthermore, the disconnect between our findings of expression of CRBN and IRF-4 in lenalidomide-treated HMCLs and patient data highlights the need for further investigation into the role of the bone marrow microenvironment on the regulation of these previously demonstrated markers of lenalidomide response. Disclosures: No relevant conflicts of interest to declare.

Expression of Interferon Regulatory Factor 4 in Chronic Myeloid Leukemia: Correlation With Response to Interferon Alfa Therapy

2000 ◽  
Vol 18 (19) ◽  
pp. 3331-3338 ◽  
Author(s):  
Manuel Schmidt ◽  
Andreas Hochhaus ◽  
Sven A. König-Merediz ◽  
Cornelia Brendel ◽  
Jutta Proba ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Myeloid Leukemia ◽  
Healthy Volunteers ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Cytogenetic Response ◽  
Interferon Regulatory Factor ◽  
Interferon Alfa ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 4

PURPOSE: Mice experiments have established an important role for interferon regulatory factor (IRF) family members in hematopoiesis. We wanted to study the expression of interferon regulatory factor 4 (IRF4) in various hematologic disorders, especially chronic myeloid leukemia (CML), and its association with response to interferon alfa (IFN-α) treatment in CML. MATERIALS AND METHODS: Blood samples from various hematopoietic cell lines, different leukemia patients (70 CML, 29 acute myeloid leukemia [AML], 10 chronic myelomonocytic leukemia [CMMoL], 10 acute lymphoblastic leukemia, and 10 chronic lymphoid leukemia patients), and 33 healthy volunteers were monitored for IRF4 expression by reverse transcriptase polymerase chain reaction. Then, with a focus on CML, the IRF4 level was determined in sorted cell subpopulations from CML patients and healthy volunteers and in in vitro–stimulated CML cells. Furthermore, IRF4 expression was compared in the CML samples taken before IFN-α therapy and in 47 additional CML samples taken during IFN-α therapy. IRF4 expression was then correlated with cytogenetic response to IFN-α. RESULTS: IRF4 expression was significantly impaired in CML, AML, and CMMoL samples. The downregulation of IRF4 in CML samples was predominantly found in T cells. In CML patients during IFN-α therapy, a significant increase in IRF4 levels was detected, and this was also observed in sorted T cells from CML patients. The increase seen during IFN-α therapy was not due to different blood counts. In regard to the cytogenetic response with IFN-α, a good response was associated with high IRF4 expression. CONCLUSION: IRF4 expression is downregulated in T cells of CML patients, and its increase is associated with a good response to IFN-α therapy. These data suggest IRF4 expression as a useful marker to monitor, if not predict, response to IFN-α in CML.

scholarly journals Identification of Potential Biomarkers and Immune Infiltration Characteristics in Idiopathic Pulmonary Arterial Hypertension Using Bioinformatics Analysis

2021 ◽  
Vol 8 ◽  
Author(s):  
Haowei Zeng ◽  
Xiaoqin Liu ◽  
Yushun Zhang
Keyword(s):  
T Cells ◽  
Pulmonary Arterial Hypertension ◽  
Mast Cells ◽  
Immune Cells ◽  
Validation Cohort ◽  
Enrichment Analysis ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Immune Infiltration ◽  
Pulmonary Arterial ◽  
Potential Biomarkers

Objectives: Idiopathic pulmonary arterial hypertension (IPAH) is a rare but severe lung disorder, which may lead to heart failure and early mortality. However, little is known about the etiology of IPAH. Thus, the present study aimed to establish the differentially expressed genes (DEGs) between IPAH and normal tissues, which may serve as potential prognostic markers in IPAH. Furthermore, we utilized a versatile computational method, CIBERSORT to identify immune cell infiltration characteristics in IPAH.Materials and Methods: The GSE117261 and GSE48149 datasets were obtained from the Gene Expression Omnibus database. The GSE117261 dataset was adopted to screen DEGs between IPAH and the control groups with the criterion of |log2 fold change| ≥ 1, adjusted P < 0.05, and to further explore their potential biological functions via Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes Pathway analysis, and Gene Set Enrichment Analysis. Moreover, the support vector machine (SVM)-recursive feature elimination and the least absolute shrinkage and selection operator regression model were performed jointly to identify the best potential biomarkers. Then we built a regression model based on these selected variables. The GSE48149 dataset was used as a validation cohort to appraise the diagnostic efficacy of the SVM classifier by receiver operating characteristic (ROC) analysis. Finally, immune infiltration was explored by CIBERSORT in IPAH. We further analyzed the correlation between potential biomarkers and immune cells.Results: In total, 75 DEGs were identified; 40 were downregulated, and 35 genes were upregulated. Functional enrichment analysis found a significantly enrichment in heme binding, inflammation, chemokines, cytokine activity, and abnormal glycometabolism. HBB, RNASE2, S100A9, and IL1R2 were identified as the best potential biomarkers with an area under the ROC curve (AUC) of 1 (95%CI = 0.937–1.000, specificity = 100%, sensitivity = 100%) in the discovery cohort and 1(95%CI = 0.805–1.000, specificity = 100%, sensitivity = 100%) in the validation cohort. Moreover, immune infiltration analysis by CIBERSORT showed a higher level of CD8+ T cells, resting memory CD4+ T cells, gamma delta T cells, M1 macrophages, resting mast cells, as well as a lower level of naïve CD4+ T cells, monocytes, M0 macrophages, activated mast cells, and neutrophils in IPAH compared with the control group. In addition, HBB, RNASE2, S100A9, and IL1R2 were correlated with immune cells.Conclusion:HBB, RNASE2, S100A9, and IL1R2 were identified as potential biomarkers to discriminate IPAH from the control. There was an obvious difference in immune infiltration between patient with IPAH and normal groups.

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