Effect of hypoxia on RAW264.7 macrophages apoptosis and signaling

Fong, Chi-Chun; Zhang, Qi; Shi, Yue-Feng; Wu, Renren; Fong, Wang-Fun; Yang, Mengsu

doi:10.1016/j.tox.2007.03.006

Cited by 19 publications

(22 citation statements)

References 48 publications

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“…It has been proven that GILZ is a mediator of GC action and plays an anti-inflammatory role at least by inhibiting NF-kBmediated activation of transcriptions in macrophages and T lymphocytes (13,30,31). In this study, we found that hypoxia significantly upregulated the expression of GILZ at both the mRNA and protein levels in macrophage RAW264.7 cells and mouse peritoneal macrophages, and the same effect on GILZ expression was found in the spleen and lung tissues of rats as well.…”

Section: Discussionsupporting

confidence: 65%

“…Furthermore, DMOG, a cellpermeable prolyl-4-hydroxylase inhibitor that can stabilize HIF1a, did not increase the expression of GILZ mRNA and protein (data not shown), suggesting that upregulation of GILZ might not be mediated by HIF-1a directly but via other signal transduction pathways or transcription factors. Because hypoxia can activate multiple signaling pathways and has been reported to activate ERK, JNK, and p38, which belong to the MAPK family and PI3K pathway in RAW264.7 cells and some other cells (13,(39)(40)(41), we investigated the effect of inhibitors of these pathways on GILZ expression in hypoxia and found that only the ERK inhibitor could markedly inhibit the expression of GILZ in hypoxia, indicating that ERK activity is involved in the induction of GILZ by hypoxia in RAW264.7 cells.…”

Section: Discussionmentioning

confidence: 99%

“…secretion (8)(9)(10)(11). Hypoxic stress could affect several independent transcriptional regulators related to adaptive and inflammatory responses, in which hypoxiainducible transcription factor-1 (HIF-1) and NF-kB are ones that play the central roles (12)(13)(14). Although the existence of the relationship between tissue hypoxia and inflammatory response is widely accepted, ways to achieve precise regulations of hypoxia on the immune cells and the exact influence of hypoxia on the inflammatory responses remain elusive.…”

mentioning

confidence: 99%

“…Therefore, GILZ is thought to be a new kind of important mediator of GC action. Recent studies have demonstrated that the anti-inflammatory and immunosuppressive roles of GILZ were achieved by inhibiting NF-kB-mediated gene transcription in macrophages and T cells (13,30,31). Some GILZ targets have been identified, including AP-1, Raf-1, and Ras, to be associated with GC effects (32,33).…”

mentioning

confidence: 99%

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Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Wang

Song

et al. 2012

The Journal of Immunology

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Hypoxia and inflammation often develop concurrently in numerous diseases, and the influence of hypoxia on natural evolution of inflammatory responses is widely accepted. Glucocorticoid-induced leucine zipper (GILZ) is thought to be an important mediator of anti-inflammatory and immune-suppressive actions of glucocorticoid (GC). However, whether GILZ is involved in hypoxic response is still unclear. In this study, we investigated the effects of hypoxic exposure and/or the administration of dexamethasone (Dex), a synthetic GC on GILZ expression both in vitro and in vivo, and further explored the relationship between GILZ and proinflammatory cytokines IL-1β, IL-6, and TNF-α under normoxic and hypoxic conditions. We found that hypoxia not only remarkably upregulated the expression of GILZ, but also significantly enhanced Dex-induced expression of GILZ in macrophages and the spleen of rats. ERK activity is found involved in the upregulation of GILZ induced by hypoxia. Inhibiting the expression of GILZ in RAW264.7 cells using specific GILZ small interfering RNA led to a significant increase in mRNA production and protein secretion of IL-1β and IL-6 in hypoxia and abrogated the inhibitory effect of Dex on expression of IL-1β and IL-6 in hypoxia. We also found that adrenal hormones played pivotal roles in upregulation of GILZ expression in vivo. Altogether, data presented in this study suggest that GILZ has an important role not only in adjusting adaptive responses to hypoxia by negatively regulating the activation of macrophages and the expression of proinflammatory cytokines, but also in mediating the anti-inflammatory action of GC under hypoxic conditions.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Wang

Song

et al. 2012

The Journal of Immunology

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“…Cells adapt to low oxygen tension by switching from an aerobic to an anaerobic glycolytic pathway for ATP production. For many cell types a major effect of hypoxia is apoptosis (18 -21) and is the response so far reported in macrophage cell lines (22)(23)(24)(25).…”

mentioning

confidence: 93%

Hypoxia Prolongs Monocyte/Macrophage Survival and Enhanced Glycolysis Is Associated with Their Maturation under Aerobic Conditions

Roiniotis

Dinh

Masendycz

et al. 2009

The Journal of Immunology

150

124

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In chronic inflammatory lesions macrophages are abundant and adapt to the low oxygen concentrations often present there. In low oxygen some cell types die by apoptosis, as reported for macrophage cell lines, while others survive better as they shift their metabolism to anaerobic glycolysis. It was found here that hypoxia prolongs the survival of murine bone marrow-derived macrophages, either in the absence or presence of low CSF-1 (M-CSF) concentrations. Although Akt activity increased in bone marrow-derived macrophages in the low oxygen conditions, the levels of both anti- and proapoptotic Bcl-2 family members decreased. Glycolysis was enhanced as judged by increased glucose uptake, glucose transporter expression, lactate dehydrogenase mRNA expression, and lactate secretion. Human monocytes responded similarly to low oxygen, and a number of genes associated with glycolysis were shown by microarray analysis and quantitative PCR to be up-regulated. Interestingly, human monocyte-derived macrophages showed evidence of enhanced glycolysis even under aerobic conditions. It is proposed that certain monocyte/macrophage populations survive better under conditions of low oxygen, thereby contributing to their increased numbers at sites of chronic inflammation and tumors; it is also proposed that as macrophages differentiate from monocytes they begin to adopt a glycolytic metabolism allowing them to adapt readily when exposed to low oxygen conditions.

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Icariin Stimulates Differentiation and Suppresses Adipocytic Transdifferentiation of Primary Osteoblasts Through Estrogen Receptor-Mediated Pathway

et al. 2016

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Icariin, the main constituent of Herba Epimedii, appears to be a promising alternative to classic drugs used to treat osteoporosis. However, the detailed molecular mechanisms of its action and the role of icariin in the cross-talk between osteoblasts and adipocytes remain unclear. The present study was designed to investigate the gene expression profile of primary osteoblasts in the presence of icariin, and the effects of icariin on the differentiation and adipogenic transdifferentiation of osteoblasts. Cellular and molecular markers expressed during osteoblastic differentiation were assessed by cytochemical analysis, real-time quantitative PCR, Western blotting, and cDNA microarray analysis. Results indicated that icariin up-regulated the expression of runt-related transcription factor 2 (Runx2), bone morphogenetic protein 2 (Bmp2), and collagen type 1 (Col1) genes, and down-regulated the expression of the peroxisome proliferator-activated receptor γ (Pparg) and CCAAT/enhancer-binding protein β (Cebpb) genes. These effects were blocked by ICI 182,780, suggesting that icariin may be acting via the estrogen receptor (ER). Results also demonstrated that the ratio of osteoprotegerin (Opg)/receptor activator of nuclear factor kappa B ligand (Rankl) expression was up-regulated following treatment with icariin. In total, osteoblastic gene expression profile analysis suggested that 33 genes were affected by icariin; these could be sub-divided into nine functional categories. It appears that icariin could stimulate the differentiation and mineralization of osteoblasts, regulate the differentiation of osteoclasts, and inhibit the adipogenic transdifferentiation of osteoblasts, therefore increasing the number of osteoblasts undergoing differentiation to mature osteoblasts, via an ER-mediated pathway. In summary, icariin may exhibit beneficial effects on bone health, especially for patients with osteoporosis and obesity.

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Effect of hypoxia on RAW264.7 macrophages apoptosis and signaling

Cited by 19 publications

References 48 publications

Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Hypoxia Prolongs Monocyte/Macrophage Survival and Enhanced Glycolysis Is Associated with Their Maturation under Aerobic Conditions

Icariin Stimulates Differentiation and Suppresses Adipocytic Transdifferentiation of Primary Osteoblasts Through Estrogen Receptor-Mediated Pathway

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