IL-1β Suppresses Prolonged Akt Activation and Expression of E2F-1 and Cyclin A in Breast Cancer Cells

Shen, Wen Hong; Jackson, Steve; Broussard, Suzanne R.; McCusker, Robert H.; Strle, Klemen; Freund, Gregory G.; Johnson, Rodney W.; Dantzer, Robert; Kelley, Keith W.

doi:10.4049/jimmunol.172.12.7272

Cited by 19 publications

(13 citation statements)

References 51 publications

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“…IL-1␤ in particular has been shown to downregulate the expression of insulin receptor substrate-1 and to inhibit Akt phosphorylation (5,17,24,27,45,52). This present study also found a substantial decline in the magnitude of insulin-induced Akt activation in the presence of IL-1␤.…”

Section: Discussionsupporting

confidence: 77%

Direct regulation of IGF-binding protein 1 promoter by interleukin-1β via an insulin- and FoxO-1-independent mechanism

Shi

Banerjee

Dobierzewska

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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kashian AA, Giltiay NV, Nikolova-Karakashian MN. Direct regulation of IGF-binding protein 1 promoter by interleukin-1␤ via an insulin-and FoxO-1-independent mechanism. Am J Physiol Endocrinol Metab 310: E612-E623, 2016. First published February 16, 2016 doi:10.1152/ajpendo.00289.2015.-The level of insulin-like growth factor-binding protein 1 (IGFBP1), a liver-produced serum protein that regulates insulin-like growth factor-I bioactivity, glucose homeostasis, and tissue regeneration, increases during inflammation. This manuscript describes a novel pathway for the regulation of hepatic IGFBP1 mRNA and protein levels by interleukin (IL)-1␤. Experiments with the luciferase reporter system show that IL-1␤ stimulates transcriptional activity from the 1-kb promoter region of IGFBP1. Although IL-1␤ stimulation suppresses the insulin activation of protein kinase B, the major upstream regulator of IGFBP1 mRNA transcription, the induction of IGFBP1 by IL-1␤ did not require an intact insulin response element. Furthermore, neither overexpression nor silencing of FoxO-1 had any effect on the IL-1␤-induced increase in IGFBP1 mRNA levels and promoter activity. However, inhibition of the ERK MAP kinases effectively prevented the IL-1␤ effects. Inhibition of neutral sphingomyelinase, a key player in the IL-1␤ signaling cascade that acts upstream of ERK, also suppressed the IL-1␤ effects, while increasing the ceramide, through the addition of C2-ceramide or via treatment with exogenous sphingomyelinase, was sufficient to induce IGFBP1 promoter-driven luciferase activity. Studies in primary rat hepatocytes where the levels of neutral sphingomyelinase were either elevated or suppressed using adenoviral constructs affirmed the key role of neutral sphingomyelinase and ceramide (exerted likely through ERK activation) in the IL-1␤-induced IGFBP1 production. Finally, the IL-1␤ effects on IGFBP1 mRNA production and protein secretion could be abolished by the addition of insulin, either at very late time points or at very high doses.ceramide; sphingomyelinase; interleukin-1␤; insulin-like growth factor-binding protein-1; inflammation INSULIN-LIKE GROWTH factor-binding proteins (IGFBPs) are a family of six serum proteins that bind to insulin-like growth factor-I (IGF-I) and regulate its turnover, transport, and tissue availability (34). Only free nonbound IGF-I is biologically active; therefore, the availability of IGFBPs modulates many of the physiological functions of IGF-I involving cellular growth, survival, proliferation, differentiation, cell motility, and glucose uptake (12). IGFBP1 is particularly important in regulating IGF-I bioactivity. It is the only IGFBP with a tightly regulated expression (21), and a strong inverse correlation exists between the levels of circulating IGFBP1 and those of free IGF-I (34, 51). High baseline IGFBP1 is found to be a reliable predictor for congestive heart failure (25) and a biomarker for early stage alcohol-induced liver disease (37). High levels of IGFBP1 have also been associated with increased...

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Section: Discussionsupporting

confidence: 77%

Direct regulation of IGF-binding protein 1 promoter by interleukin-1β via an insulin- and FoxO-1-independent mechanism

Shi

Banerjee

Dobierzewska

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…In addition, lymphotoxin, TNF-a, NO, and ROS can directly kill cells. TNF-a has been shown to induce the death of neurons via a direct apoptotic effect after receptor binding and by directly interfering with intracellular substrates used by growth factors such as IGF-I and the insulin receptor (Shen et al, 2004;Venters et al, 1999). Elevated cytokines activate microglia, thereby stimulating a cycle of inflammation that recruits leukocytes, causes vascular breakdown, and directly induces cell death through the release of cytotoxic substances.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis

Ghoshal

Das

Ghosh

et al. 2007

Glia

345

354

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While a number of studies have documented the importance of microglia in central nervous system (CNS) response to injury, infection and disease, little is known regarding its role in viral encephalitis. We therefore, exploited an experimental model of Japanese Encephalitis, to better understand the role played by microglia in Japanese Encephalitis Virus (JEV) infection. Lectin staining performed to assess microglial activation indicated a robust increase in reactive microglia following infection. A difference in the topographic distribution of activated, resting, and phagocytic microglia was also observed. The levels of various proinflammatory mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (Cox-2), IL-6, IL-1beta, TNF-alpha, and MCP-1 that have been implicated in microglial response to an activational state was significantly elevated following infection. These cytokines exhibited region selective expression in the brains of infected animals, with the highest expression observed in the hippocampus. Moreover, the expression of neuronal specific nuclear protein NeuN was markedly downregulated during progressive infection indicating neuronal loss. In vitro studies further confirmed that microglial activation and subsequent release of various proinflammatory mediators induces neuronal death following JEV infection. Although initiation of immune responses by microglial cells is an important protective mechanism in the CNS, unrestrained inflammatory responses may result in irreparable brain damage. Our findings suggest that the increased microglial activation following JEV infection influences the outcome of viral pathogenesis. It is likely that the increased microglial activation triggers bystander damage, as the animals eventually succumb to infection.

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“…I mmune reactions as well as direct proliferative and antiproliferative effects of cytokines or cytokine-related mediators participate in the natural course of cancer (1)(2)(3)(4)(5). The recently discovered cytokine IL-22, which is structurally related to IL-10 (6), was identified as a T cell-derived inducible factor produced by IL-9-activated murine T cells (7).…”

Section: Il-22-mediated Tumor Growth Reduction Correlates With Inhibimentioning

confidence: 99%

“…Consequently, IL-22 does not induce STAT3 phosphorylation in eEND2 cells. We then studied signaling pathways involved in cell cycle control, cell proliferation and tumor growth such as ERK1/2 and AKT phosphorylation (1,15,16,(35)(36)(37)(38). IL-22 significantly inhibited these signaling pathways as shown by immunoblot analysis.…”

Section: Il-22 Activates Stat3 and Inhibits Erk1/2 And Akt Phosphorylmentioning

confidence: 99%

IL-22-Mediated Tumor Growth Reduction Correlates with Inhibition of ERK1/2 and AKT Phosphorylation and Induction of Cell Cycle Arrest in the G2-M Phase

Weber

Gaertner

Erl

et al. 2006

The Journal of Immunology

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IL-22 is a recently discovered cytokine of the IL-10 family that binds to a class II cytokine receptor composed of IL-22R1 and IL-10R2c and influences a variety of immune reactions. As IL-22 has also been shown to modulate cell cycle and proliferation mediators such as ERK1/2 and JNK, we studied the role of IL-22 in proliferation, apoptosis, and cell cycle regulation in EMT6 murine breast cancer cells in vitro and in vivo. In this study, we report that murine breast cancer cells express functional IL-22R as indicated by RT-PCR studies, immunoblotting, and STAT3 activation assays. Importantly, IL-22 exposure of EMT6 cells resulted in decreased levels of phosphorylated ERK1/2 and AKT protein kinases, indicating an inhibitory effect of IL-22 on signaling pathways promoting cell proliferation. Furthermore, IL-22 induced a cell cycle arrest of EMT6 cells in the G2-M phase. IL-22 reduced EMT6 cell numbers and the proliferation rate by ∼50% as measured by [3H]thymidine incorporation. IL-22 treatment of EMT6 tumor-bearing mice lead to a decreased tumor size and a reduced tumor cell proliferation in vivo, as determined by 3′-deoxy-3′-fluorothymidine-positron emission tomography scans. Interestingly, IL-22 did not induce apoptosis, as determined in annexin V binding assay and caspase-3 activation assay and had no effect on angiogenesis in vivo. In conclusion, our results indicate that IL-22 reduced tumor growth by inhibiting signaling pathways such as ERK1/2 and AKT phosphorylation that promote tumor cell proliferation in EMT6 cells. Therefore, IL-22 may play a role in the control of tumor growth and tumor progression.

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IL-1β Suppresses Prolonged Akt Activation and Expression of E2F-1 and Cyclin A in Breast Cancer Cells

Cited by 19 publications

References 51 publications

Direct regulation of IGF-binding protein 1 promoter by interleukin-1β via an insulin- and FoxO-1-independent mechanism

Direct regulation of IGF-binding protein 1 promoter by interleukin-1β via an insulin- and FoxO-1-independent mechanism

Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis

IL-22-Mediated Tumor Growth Reduction Correlates with Inhibition of ERK1/2 and AKT Phosphorylation and Induction of Cell Cycle Arrest in the G2-M Phase

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