Gene expression changes caused by the IRAK1/IRAK4 inhibitor R191 in cell lines of Waldenström’s macroglobulinemia
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PROVIDER: PRJNA416783 | ENA |
REPOSITORIES: ENA
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Project description:The L265P mutation in MYD88 is very frequent in tumor cells of Waldenström’s macroglobulinemia (WM), and activates NF-kappaB through IRAK1 and IRAK4. We examined the effect of the IRAK1/4 inhibitor R191 on two cell lines of WM. Gene expression profiling suggested that R191 reduced activity of AKT and mTOR signaling, consistent with other assays and functional studies. Other changes suggested reduced proliferation and MYC activity, and an ER stress response.
2019-11-01 | GSE106409 | GEO
Project description:Analysis of HT-1080 fibrosarcoma cells transcriptome following 4 hours treatment with IRAK4 inhibitor was performed. Results provide insight into mode of action of IRAK4 inhibitor under study. Project co-financed from European Regional Development Fund under The Operational Program Innovative Economy, 2007-2013, measure 1.4 (UDA-POIG.01.04.00-12-049/11-00)
2018-11-24 | GSE122844 | GEO
Project description:Analysis of HT-1080 fibrosarcoma cells transcriptome following 24 hours treatment with IRAK4 inhibitor was performed. Results provide insight into mode of action of IRAK4 inhibitor under study. Project co-financed from European Regional Development Fund under The Operational Program Innovative Economy, 2007-2013, measure 1.4 (UDA-POIG.01.04.00-12-049/11-00)
2018-11-24 | GSE122845 | GEO
Project description:IRAK4 kinase plays a critical role in innate immune responses and inflammation by modulating the TLR/IL-1R signaling pathway, yet the mechanism by which it regulates downstream pathways and transcription factors to induce inflammatory cytokines is unclear. IRAK4 can mediate signaling events by mechanisms both dependent and independent of its kinase activity. Understanding this regulation is important for deciphering the role of IRAK4 and for the development of treatments for inflammatory diseases and cancer. Through transcriptomic and biochemical analyses of primary human monocytes treated with a highly potent and selective inhibitor of IRAK4, we show that IRAK4 kinase activity controls the transcription factor IRF5 which in turn induces inflammatory cytokine and type I interferon transcription in myeloid cells. We also show that IRAK4 kinase activity does not control activation of NF-κB. Following TLR stimulation, translocation of IRF5, but not NF-κB, to the nucleus in human monocytes is abolished by IRAK4 kinase inhibition. In addition, binding of IRF5, but not NF-κB p65, to promoters of inflammatory target genes (TNF-α and IP10) is blocked with an IRAK4 kinase inhibitor. IKKβ, a known activator of IRF5, is phosphorylated in response to TLR mediated signaling, and inhibition of IRAK4 kinase blocks IKKβ phosphorylation. Pharmacological inhibition of IKKβ and TAK1, the upstream kinase of IKKβ, in human monocytes blocks IL-1, IL-6 and TNF-α cytokine production, as well as IRF5 translocation to the nucleus. Taken together, our data suggest a novel mechanism by which IRAK4 kinase activity regulates TAK1 and IKKβ activation, leading to the translocation of IRF5 and induction of inflammatory cytokines in human monocytes.
2017-10-12 | GSE86234 | GEO
Project description:We perform CRISPR knockout of IRAK4 usig two different sgRNAs in murine KP2 cells, and then reexpressed murine IRAK4 in these two KO cell lines. We performed RNAseq on wild-type, IRAK4 KO and IRAK4 KO/rescue cell lines to investigate pathways contolled by IRAK4.
2020-09-02 | GSE148442 | GEO
Project description:Genes regulated in HT-1080 cells after treatment with IRAK4 inhibitor
| PRJNA506896 | ENA
Project description:Here were provide RNA-seq from MRL, MRL-IRAK4-KinaseDead(KD), IRAK4-KD, and C57BL6/J mouse hippocampi of 10 month old mice
2024-04-16 | GSE264121 | GEO
Project description:In this study, we evaluated clonal Waldenström macroglobulinemia cells with mapping of maturation stages of B cell lymphomagenesis concurrently with the innate and adaptive immune tumor microenvironment in active WM patients (newly diagnosed (NDWM, n = 19) and relapsed or relapsed/refractory (RRWM, n = 42) compared to 10 healthy donors (HD) by mass cytometry.
2022-12-13 | PXD038388 | Pride
Project description:Exciting discoveries related to IL-1R/TLR signaling in development of atherosclerosis plaque have triggered intense interest in the molecular mechanisms by which innate immune signaling modulates the onset and development of atherosclerosis. Previous studies have clearly shown the definitive role of proinflammatory cytokine IL-1 in the development of atherosclerosis. Recent studies have provided direct evidence supporting a link between innate immunity and atherogenesis. While it is still controversial about whether infectious pathogens contribute to cardiovascular diseases, direct genetic evidence indicates the importance of IL-1R/TLR signaling in atherogenesis. In this study, we examined the role of IRAK4 kinase activity in modified LDL-mediated signaling using bone marrow-derived macrophage as well as in vivo model of atherosclerosis. First, we found that the IRAK4 kinase activity was required for modified LDL-induced NFκB activation and expression of a subset of proinflammatory genes, but not for the activation of MAPKs in bonemarrow-derived macrophage. IRAK4 kinase inactive knock-in (IRAK4KI) mice were bred onto ApoE-/- mice to generate IRAK4KI/ApoE-/- mice. Importantly, the aortic sinus lesion formation was impaired in IRAK4KI/ApoE-/- mice compared to that in ApoE-/- mice. Furthermore, proinflammatory cytokine production was reduced in the aortic sinus region of IRAK4KI/ApoE-/- mice compared to that in ApoE-/- mice. Taken together, our results indicate that the IRAK4 kinase plays an important role in modified LDL-mediated signaling and the development of atherosclerosis, suggesting that pharmacological inhibition of IRAK4 kinase activity might be a feasible approach in the development of anti-atherosclerosis drugs. To identify global changes in gene expression, we examined gene expression profiles of macrophages from wild-type and IRAK4 kinase-inactive knock-in mice in response to acLDL stimulation using the Illumina microarray with probes for 23,000 transcripts. Bone marrow-derived macrophages from wild-type and IRAK4 kinase-inactive knock-in mice were treated with acLDL for 24 hours.
2010-10-23 | E-GEOD-24894 | biostudies-arrayexpress
Project description:Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but so far success remains limited in the clinic. Furthermore, preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAFs) carries a risk of accelerating PDAC progression. These concerns underscore the need to concurrently target the key signaling mechanisms that drive the malignant attributes of both CAFs and PDAC cells. We previously reported that inhibition of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) suppresses NF-kB activity and promotes chemotherapy response in PDAC cells. In this study, we show that CAFs in PDAC tumors robustly express activated IRAK4 and NF-kb. The role of IRAK4 and NF-kB in PDAC CAFs has not been reported, and should be clarified before advancing IRAK4 inhibitors to the clinic. Using shRNAs and small molecular inhibitors, we found that IRAK4 is a key driver of NF-kB activity in CAFs. We showed that CAFs utilizes IRAK4 to drive tumor fibrosis, support PDAC cells proliferation, survival and chemoresistance in vitro and in vivo. From cytokine array analysis of CAFs and microarray analysis of PDAC cells, we identified IL-1b as a key cytokine that activates IRAK4 in CAFs. Targeting IRAK4 or IL-1b renders PDAC tumors less fibrotic and more sensitive to gemcitabine in vivo. Moreover, high IL-1b expression by immunohistochemistry in PDAC stroma is strongly associated with poor overall survival. Together, our studies established a tumor-stroma IL-1b-IRAK4 feedforward circuitry that can be therapeutically disrupted to render chemotherapy more effective in PDAC.
2018-01-26 | GSE73046 | GEO