CD40 Stimulates a “Feed-Forward” NF-κB–Driven Molecular Pathway That Regulates IFN-β Expression in Carcinoma Cells

Moschonas, Aristides; Ioannou, Marina; Eliopoulos, Aristides G.

doi:10.4049/jimmunol.1200133

Cited by 22 publications

(16 citation statements)

References 53 publications

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“…NF-κB and IRF1 were activated in MΦ+RM1(HA) but not in MΦ+MC4(HA) cocultures. Both transcription factors activate inflammatory responses and in some contexts cooperate with the activation of proinflammatory cytokines (21,22). These findings correlate with the differential inflammatory response of macrophages in the cocultures with the apoptotic prostate cancer RM1 and the noncancer MC4 cells (Figure 1, A-C).…”

Section: Proinflammatory Cytokines Are Induced In Macrophages Upon Apsupporting

confidence: 64%

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

Roca

Jones

Purica

et al. 2017

Journal of Clinical Investigation

113

110

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Section: Proinflammatory Cytokines Are Induced In Macrophages Upon Apsupporting

confidence: 64%

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

Roca

Jones

Purica

et al. 2017

Journal of Clinical Investigation

113

110

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“…Interestingly, Moschonas has indicated that stimulation of CD40 by its ligand has promoted the expression of IFN-β through the binding IRF7 to its promoter. IRF7 is a transcriptional factor which regulates the expression of type I interferon [48]. Silencing of IRF7 pathways in breast cancer accelerated bone metastasis through immune escape [49].…”

Section: Discussionmentioning

confidence: 99%

Global transcriptome-wide analysis of CIK cells identify distinct roles of IL-2 and IL-15 in acquisition of cytotoxic capacity against tumor

et al. 2014

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BackgroundCytokine-induced killer (CIK) cells are an emerging approach of cancer treatment. Our previous study have shown that CIK cells stimulated with combination of IL-2 and IL-15 displayed improved proliferation capacity and tumor cytotoxicity. However, the mechanisms of CIK cell proliferation and acquisition of cytolytic function against tumor induced by IL-2 and IL-15 have not been well elucidated yet.MethodsCIKIL-2 and CIKIL-15 were generated from peripheral blood mononuclear cells primed with IFN-γ, and stimulated with IL-2 and IL-15 in combination with OKT3 respectively. RNA-seq was performed to identify differentially expressed genes, and gene ontology and pathways based analysis were used to identify the distinct roles of IL-2 and IL-15 in CIK preparation.ResultsThe results indicated that CIKIL-15 showed improved cell proliferation capacity compared to CIKIL-2. However, CIKIL-2 has exhibited greater tumor cytotoxic effect than CIKIL-15. Employing deep sequencing, we sequenced mRNA transcripts in CIKIL-2 and CIKIL-15. A total of 374 differentially expressed genes (DEGs) were identified including 175 up-regulated genes in CIKIL-15 and 199 up-regulated genes in CIKIL-2. Among DEGs in CIKIL-15, Wnt signaling and cell adhesion were significant GO terms and pathways which related with their functions. In CIKIL-2, type I interferon signaling and cytokine-cytokine receptor interaction were significant GO terms and pathways. We found that the up-regulation of Wnt 4 and PDGFD may contribute to enhanced cell proliferation capacity of CIKIL-15, while inhibitory signal from interaction between CTLA4 and CD80 may be responsible for the weak proliferation capacity of CIKIL-2. Moreover, up-regulated expressions of CD40LG and IRF7 may make for improved tumor cytolytic function of CIKIL-2 through type I interferon signaling.ConclusionsThrough our findings, we have preliminarily elucidated the cells proliferation and acquisition of tumor cytotoxicity mechanism of CIKIL-15 and CIKIL-2. Better understanding of these mechanisms will help to generate novel CIK cells with greater proliferation potential and improved tumor cytolytic function.

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“…Non-canonical NFκB signaling is slow but persistent and requires de novo NIK protein synthesis and NIK stabilization [58]. It is activated by receptors that belong to the TNFR (tumor necrosis factor receptor) superfamily like BAFF (B-cell-activating factor), CD40 or lymphotoxin β-receptor (LTβR) [59][60][61][62].…”

Section: The Non-canonical Nfκb Signaling Pathwaymentioning

confidence: 99%

The Role of an NFκB-STAT3 Signaling Axis in Regulating the Induction and Maintenance of the Pluripotent State

Agarwal¹,

Zambidis²

2014

Pluripotent Stem Cell Biology - Advances in Mechanisms, Methods and Models

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Multipotent myeloid progenitors are derived from hematopoietic stem cells and differentiate to monocytes macrophages, dendritic cells, and granulocytes, which elicit the initial innate immune response toward pathogens [41]. NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a central transcription factor that regulates these innate immune responses during microbial infections [42-44]. The NFκB system belongs to a group of early-acting transcription factors that are present in the cytoplasm in an inactive state but can be quickly activated by multiple inflammatory stimuli [45, 46]. 2.1. The canonical NFκB signaling pathway The NFκB family consists of 5 members; p65 (RelA), p50 and c-Rel are involved in canonical signaling, and p52 and RelB are involved in non-canonical signaling. Canonical NFκB signaling is characterized by activation of the IκB kinase complex (IKK), which contains two kinases, IKK1/α and IKK2/β along with a non-catalytic subunit called IKKγ (NEMO) [47, 48]. Unstimulated NFκB is sequestered in the cytoplasm by IκBα protein. In contrast, activation of the IKK complex (e.g., by TLRs) leads to IKKβ-mediated serine phosphorylation of IκBα triggering its proteasome-mediated degradation and its dissociation from NFκB [49, 50]. This activates the p65:p50 dimer through p65 phosphorylation and leads to NFκB translocation into the nucleus where it induces target gene expression. Subsequent acetylation keeps p65 in the nucleus [51]. This can be reverted by HDAC3 (histone deacetylase 3)-induced deacetylation of p65, which increases the affinity of NFκB proteins for IκBα and nuclear export [52, 53]. Canonical NFκB signaling is a fast and transient process that regulates complex inflammatory processes that includes the initial pro-inflammatory phase, the induction of apoptosis, and even tumorigenesis [54]. It can be activated by toll-like receptors (TLR), which recognize characteristic pathogenic molecules to activate innate immune responses [55-57].

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CD40 Stimulates a “Feed-Forward” NF-κB–Driven Molecular Pathway That Regulates IFN-β Expression in Carcinoma Cells

Cited by 22 publications

References 53 publications

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

Global transcriptome-wide analysis of CIK cells identify distinct roles of IL-2 and IL-15 in acquisition of cytotoxic capacity against tumor

The Role of an NFκB-STAT3 Signaling Axis in Regulating the Induction and Maintenance of the Pluripotent State

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