Monocyte Survival Factors Induce Akt Activation and Suppress Caspase-3

Goyal, Anuj; Wang, Yijie; Graham, Mandy M.; Doseff, Andrea I.; Bhatt, Nitin; Marsh, Clay B.

doi:10.1165/ajrcmb.26.2.4640

Cited by 82 publications

(84 citation statements)

References 39 publications

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“…We previously observed that, whereas CpG DNA, LPS, and CSF-1 all efficiently activated ERK1/2, CpG DNA and LPS were relatively poor inducers of Akt phosphorylation compared with CSF-1 in BMM (45). Consistent with these findings in mouse macrophages, CSF-1 was also a more potent activator of Akt kinase activity than other survival factors, including LPS, in human monocytes (18). Despite these comparatively weak effects of bacterial products on Akt activation, we have shown that the PI3K inhibitor LY294002, which prevented Akt phosphorylation in BMM (data not shown), inhibited survival in response to LPS, CpG DNA, and CSF-1.…”

Section: Discussionsupporting

confidence: 68%

CpG DNA Activates Survival in Murine Macrophages through TLR9 and the Phosphatidylinositol 3-Kinase-Akt Pathway

Sester

Brion

Trieu

et al. 2006

The Journal of Immunology

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Bacterial CpG-containing (CpG) DNA promotes survival of murine macrophages and triggers production of proinflammatory mediators. The CpG DNA-induced inflammatory response is mediated via TLR9, whereas a recent study reported that activation of the Akt prosurvival pathway occurs via DNA-dependent protein kinase (DNA-PK) and independently of TLR9. We show, in this study, that Akt activation and survival of murine bone marrow-derived macrophages (BMM) triggered by CpG-containing phosphodiester oligodeoxynucleotides or CpG-containing phosphorothioate oligodeoxynucleotides was completely dependent on TLR9. In addition, survival triggered by CpG-containing phosphodiester oligodeoxynucleotides was not compromised in BMM from SCID mice that express a catalytically inactive form of DNA-PK. CpG DNA-induced survival of BMM was inhibited by the PI3K inhibitor, LY294002, but not by the MEK1/2 inhibitor, PD98059. The effect of LY294002 was specific to survival, because treatment of BMM with LY294002 affected CpG DNA-induced TNF-α production only modestly. Therefore, CpG DNA activates macrophage survival via TLR9 and the PI3K-Akt pathway and independently of DNA-PK and MEK-ERK.

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Section: Discussionsupporting

confidence: 68%

CpG DNA Activates Survival in Murine Macrophages through TLR9 and the Phosphatidylinositol 3-Kinase-Akt Pathway

Sester

Brion

Trieu

et al. 2006

The Journal of Immunology

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“…However, IFN-␤ treatment did not induce apoptosis, and the effect of LPS on apoptosis in macrophages is also still controversial (19,22). Recently, LPS was reported to induce apoptosis often in a cell type-specific manner and sometimes to show an antiapoptotic effect in monocytes, neutrophils, and macrophages (22,(31)(32)(33)(34). We also observed the similar results (LPS did not increase the apoptotic cell populations) in macrophages using flow cytometric analysis (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Bacterial Endotoxin Induces the Release of High Mobility Group Box 1 via the IFN-β Signaling Pathway

Kim

Lee

et al. 2009

The Journal of Immunology

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Sepsis is a devastating condition characterized by a systemic inflammatory response. Recently, high mobility group box 1 (HMGB1) was identified as a necessary and sufficient mediator of the lethal systemic inflammation caused by sepsis. However, despite its clinical importance, the mechanism of HMGB1 release has remained to be elusive. In this study, we demonstrate that the IFN-β-mediated JAK/STAT pathway is essential for LPS or Escherichia coli-induced HMGB1 release, which is dependent on Toll/IL-1R domain-containing adapter-inducing IFN-β adaptor. Additionally, we show that NO acts as a downstream molecule of the IFN-β signaling. Furthermore, the JAK inhibitor treatment as well as the STAT-1 or IFN-β receptor deficiency reduced HMGB1 release in a murine model of endotoxemia. Our results suggest that HMGB1 release in sepsis is dependent on the IFN-β signaling axis; thus, therapeutic agents that selectively inhibit IFN-β signaling could be beneficial in the treatment of sepsis.

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“…ERK, NFB-p50, JAK1, and AKT are key survival mediators, which are activated in response to inflammation and have previously been shown to inhibit caspase activation and promote monocyte differentiation (27)(28)(29)(30). Therefore, we examined the activation of these potential survival molecules by Western blotting.…”

Section: Characterization Of Cancer Cell-derived Exosomes and Theirmentioning

confidence: 99%

Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases

Song

Ding

Liu

et al. 2016

Journal of Biological Chemistry

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Tumor-associated macrophages (TAM) play pivotal roles in cancer initiation and progression. Monocytes, the precursors of TAMs, normally undergo spontaneous apoptosis within 2 days, but can subsist in the inflammatory tumor microenvironment for continuous survival and generation of sufficient TAMs. The mechanisms underlying tumor-driving monocyte survival remain obscure. Here we report that cancer cell-derived exosomes were crucial mediators for monocyte survival in the inflammatory niche. Analysis of the survival-promoting molecules in monocytes revealed that cancer cell-derived exosomes activated Ras and extracellular signalregulated kinases in the mitogen-activated protein kinase (MAPK) pathway, resulting in the prevention of caspase cleavage. Phosphorylated receptor tyrosine kinases (RTKs), such as phosphorylated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), were abundantly expressed in cancer cell-derived exosomes. Knock-out of EGFR or/and HER-2, or alternatively, inhibitors against their phosphorylation significantly disturbed the exosome-mediated activation of the MAPK pathway, inhibition of caspase cleavage, and increase in survival rate in monocytes. Moreover, the deprived survival-stimulating activity of exosomes due to null expression of EGFR and HER-2 could be restored by activation of another RTK, insulin receptor. Overall, our study uncovered a mechanism of tumor-associated monocyte survival and demonstrated that cancer cell-derived exosomes can stimulate the MAPK pathway in monocytes through transport of functional RTKs, leading to inactivation of apoptosis-related caspases. This work provides insights into the long sought question on monocyte survival prior to formation of plentiful TAMs in the tumor microenvironment.Clinical and experimental evidences suggest that a particular type of macrophage population is present within the tumor microenvironment (1). Tumor-associated macrophages (TAMs) 4 are derived from recruited monocytes or resident tissue macrophages (2), and play essential roles in tumor initiation, progression, and metastasis (3). Monocyte recruitment, survival, and differentiation are fundamental steps for continuous generation of TAMs. Previous studies are focused on understanding the complicated mechanisms of monocyte recruitment and differentiation within tumor tissues (2). However, investigations regarding how monocytes maintain survival before differentiation into sufficient TAMs have never been reported.As key components of the innate immune system, monocytes are continuously produced by bone marrow but normally undergo spontaneous apoptosis within 48 h in blood circulation (4, 5). Monocyte apoptosis can be prevented in vitro by serum at high concentrations (Ͼ20%), differentiation factors, and a wide range of inflammatory stimuli such as lipopolysaccharide (LPS) and interferon-␥ (IFN-␥), all of which reduce the activation of caspases and trigger the differentiation of monocytes into macrophages or dendritic cells (5-10). However, i...

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Monocyte Survival Factors Induce Akt Activation and Suppress Caspase-3

Cited by 82 publications

References 39 publications

CpG DNA Activates Survival in Murine Macrophages through TLR9 and the Phosphatidylinositol 3-Kinase-Akt Pathway

CpG DNA Activates Survival in Murine Macrophages through TLR9 and the Phosphatidylinositol 3-Kinase-Akt Pathway

Bacterial Endotoxin Induces the Release of High Mobility Group Box 1 via the IFN-β Signaling Pathway

Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases

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