Sensitizing leukemia stem cells to NF-κB inhibitor treatment <i>in vivo</i> by inactivation of both TNF and IL-1 signaling

Li, Jing; Volk, Andrew; Zhang, Jun; Cannova, Joseph; Dai, Shaojun; Hao, Caiqin; Hu, Chenglong; Sun, Jiewen; Xu, Yan; Wei, Wei; Breslin, Peter; Nand, Sucha; Chen, Jianjun; Kini, Ameet R.; Zhu, Jiang; Zhang, Jiwang

doi:10.18632/oncotarget.14220

Cited by 33 publications

(23 citation statements)

References 55 publications

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“…As a result, IRAK1/4 inhibitor treatment caused increased survival and impaired LSC function in the MLL-AF9 mouse model of AML ( 97 ). This novel mechanism could account for some of the activity of IL-1 pathway inhibitors reported in other studies in secondary AML, and specifically in MLL-AF9 AML ( 98 ). Together, these results suggest that there may be differences in how leukemic blasts and LSCs regulate IL-1β expression and respond to IL-1β, and that there may be differential dose-dependent effects of IL-1β on both normal HSPCs and LSCs.…”

Section: Il-1βmentioning

confidence: 60%

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

2017

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Hematopoietic stem cells (HSCs) are a rare subset of bone marrow cells that usually exist in a quiescent state, only entering the cell cycle to replenish the blood compartment, thereby limiting the potential for errors in replication. Inflammatory signals that are released in response to environmental stressors, such as infection, trigger active cycling of HSCs. These inflammatory signals can also directly induce HSCs to release cytokines into the bone marrow environment, promoting myeloid differentiation. After stress myelopoiesis is triggered, HSCs require intracellular signaling programs to deactivate this response and return to steady state. Prolonged or excessive exposure to inflammatory cytokines, such as in prolonged infection or in chronic rheumatologic conditions, can lead to continued HSC cycling and eventual HSC loss. This promotes bone marrow failure, and can precipitate preleukemic states or leukemia through the acquisition of genetic and epigenetic changes in HSCs. This can occur through the initiation of clonal hematopoiesis, followed by the emergence preleukemic stem cells (pre-LSCs). In this review, we describe the roles of multiple inflammatory signaling pathways in the generation of pre-LSCs and in progression to myelodysplastic syndrome (MDS), myeloproliferative neoplasms, and acute myeloid leukemia (AML). In AML, activation of some inflammatory signaling pathways can promote the cycling and differentiation of LSCs, and this can be exploited therapeutically. We also discuss the therapeutic potential of modulating inflammatory signaling for the treatment of myeloid malignancies.

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Section: Il-1βmentioning

confidence: 60%

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

2017

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“…After the NF-κB pathway was activated, the gene transcription of an array of pro-inflammatory mediators and inflammatory cytokines, including IL-1b and TNF-α, is induced. 29 It has been reported that NF-κB pathway downregulates the expression of AQP5 in AR rats, by inhibiting p-CREB. Wang et al 19 showed that this signal cascade works through increased transcription of IL-1b while Skowron-zwarg et al 30 demonstrated that TNF-α was involved and suppressed cAMP-response element-dependent gene expression by competitive binding to CREB-binding protein.…”

Section: Discussionmentioning

confidence: 99%

Chlorpheniramine attenuates histamine-mediated aquaporin 5 downregulation in human nasal epithelial cells via suppression of NF-κB activation

Chang¹,

Lin²,

Wang³

et al. 2017

Int. J. Med. Sci.

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Background: Aquaporin 5 (AQP5) is most likely the primary water channel in the human nasal mucosa and acts as a key tight junction protein. The signaling cascades responsible for AQP5 regulation are still works in progress.Objective: This study sought to determine the effects of histamine and chlorpheniramine on AQP5 expression in human nasal epithelial cells (HNEpC) and to detect the signaling cascades responsible for these effects.Methods: HNEpC were cultured with four concentrations of histamine or chlorpheniramine in vitro. The sub-cellular distribution of AQP5 was explored using immunocytochemistry. The pharmacologic effects of histamine and chlorpheniramine on the expression of the phosphorylation of cyclic adenosine monophosphate-responsive element binding protein (p-CREB), the AQP5 and the NF-κB protein were examined using Western blotting.Results: AQP5 was found to be located in cell membrane and cytoplasm and present in every group without significant difference. Histamine inhibits the expression of AQP5 and p-CREB in HNEpC, while chlorpheniramine dose-dependently increases these protein levels with statistical significance. HNEpC treated with histamine and chlorpheniramine in turn showed the same trends as those intervened separately with these two drugs. Moreover, chlorpheniramine had the ability to reverse the inhibitory effect of histamine. Western blotting analysis revealed that after incubation with 10-4 M histamine, NF-κB protein was significantly heightened by 165% compared with the untreated control group. Again, such increase can be significantly reversed after chlorpheniramine treatment.Conclusions: The current study demonstrated that histamine inhibits CREB phosphorylation in HNEpC, which results in decreased AQP5 expression via activation of NF-κB pathway. Chlorpheniramine attenuates the inhibitory effect of histamine in p-CREB/AQP5 expression via suppression of NF-κB signal cascades. This observation could provide additional insight into the anti-inflammatory effects of H1-antihistamines that contribute to maintain airway surface liquid and mucosal defense.

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“…The first approach could ameliorate the clinical progress in CIA more than the single treatments did [395]. Additionally, RA patients were treated with the combination of IL1 and TNF neutralizing drugs although this therapy did not have added value [396], although this strategy seemed promising in preclinical sepsis models and in acute myeloid leukemia [76,397]. However, the complete blockage of host defense mechanisms should be kept in mind as a plausible destructive side effect.…”

Section: Multispecific Approachesmentioning

confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

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Sensitizing leukemia stem cells to NF-κB inhibitor treatment in vivo by inactivation of both TNF and IL-1 signaling

Cited by 33 publications

References 55 publications

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

Inflammatory Signaling Pathways in Preleukemic and Leukemic Stem Cells

Chlorpheniramine attenuates histamine-mediated aquaporin 5 downregulation in human nasal epithelial cells via suppression of NF-κB activation

A New Venue of TNF Targeting

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