Ceramide-induced nuclear translocation of NF-κB is a potential mediator of the apoptotic response to TNF-α in murine clonal osteoblasts

Kitajima, Isao; Soejima, Yasuko; Takasaki, Ikuko; Beppu, Hidehiko; Tokioka, T; Maruyama, Ikuro

doi:10.1016/8756-3282(96)00181-0

Cited by 121 publications

(72 citation statements)

References 32 publications

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“…However, we found a diminished TNF-␣ and IL-6 production when ceramide synthesis or NF-B activation was blocked. Together with previous reports stating that ceramide induces NF-B activation (17,19,85,86) and the fact that the transcription of TNF-␣ and IL-6 is controlled by NF-B, we propose that the age-associated up-regulation of both ceramide and NF-B work sequentially to promote the production of inflammatory molecules. These inflammatory molecules, in turn, contribute to the induction of insulin resistance, a key factor in the etiology of T2D.…”

Section: Discussionmentioning

confidence: 85%

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Ren

Pae

et al. 2007

The Journal of Immunology

247

209

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The incidence of type 2 diabetes (T2D) increases with age. Low‐grade inflammation in AT is implicated in development of insulin resistance and T2D. We conducted a study to determine if inflammatory responses are upregulated with age in AT. Results show that visceral AT from old mice had significantly higher expression of mRNA levels of IL‐1β, IL‐6, TNF‐α, and COX‐2 than those of young mice (263, 208, 165, and 73%, higher respectively). In determining the relative contribution of different components of AT to these age‐related changes, we found that adipocytes (AD) from old mice produced significantly more (2 to 3 folds) IL‐6 and PGE2 than those from young mice while no significant age difference was observed in their production by stromal vascular cells. There was no significant effect of age on number of Mϕ/g AT and Mϕ of either age group produced significantly more IL‐6 when incubated in conditioned medium from old AD compared to that of young. Blocking NF‐κB activation reduced IL‐6 production while addition of ceramide or sphingomyelinase increased IL‐6 production in young AD to a level comparable to that of old AD. Inhibiting de novo ceramide synthesis reduced IL‐6 production by AD. NF‐κB regulates expression of inflammatory products including COX‐2 and IL‐6. Ceramide was shown to increase COX‐2 expression in aged Mϕ through NF‐κB activation. Thus, these data suggest a potential role for ceramide and NF‐κB in the age‐related increase of AT inflammation. Further research is needed to fully determine the underlying mechanisms of the observed effects and their contribution to T2D in the aged. Supported by USDA #58‐1950‐9‐001 and NIA #R01 AG009140‐10A1.

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Section: Discussionmentioning

confidence: 85%

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Ren

Pae

et al. 2007

The Journal of Immunology

247

209

View full text Add to dashboard Cite

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“…(15) Many studies have provided evidence for TNF-a's apoptotic action in osteoblasts. (33)(34)(35) TNF-a also can augment apoptotic stimuli that are induced by Fas ligand or cycloheximide. (36) In osteoblastic cells, TNF-a's main apoptotic effects are mediated by tumor necrosis factor receptor 1 (TNFR1) and lead to the recruitment of TNFR1-associated death domain, which serves as a platform for generating various signaling complexes.…”

Section: Discussionmentioning

confidence: 99%

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Ghali

Chauveau

Hardouin

et al. 2010

Journal of Bone and Mineral Research

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RUNX2 is a bone-specific transcription factor that plays a critical role in prenatal bone formation and postnatal bone development. It regulates the expression of genes that are important in committing cells into the osteoblast lineage. There is increasing evidence that RUNX2 is involved in osteoblast proliferation. RUNX2 expression increases during osteoblast differentiation, and recent data even suggest that it acts as a proapoptotic factor. The cytokine tumor necrosis factor a (TNF-a) is known to modulate osteoblast functions in a manner that depends on the differentiation stage. TNF-a affects the rate at which mesenchymal precursor cells differentiate into osteoblasts and induces apoptosis in mature osteoblasts. Thus we sought to establish whether or not the effects of TNF-a and fetal calf serum on proliferation and apoptosis in human mesenchymal stem cells (hMSCs) were dependent on RUNX2 level and activity. We transfected hMSCs with small interfering RNAs (siRNAs) directed against RUNX2 and found that they proliferated more quickly than control hMSCs transfected with a nonspecific siRNA. This increase in proliferation was accompanied by a rise in cyclin A1, B1, and E1 expression and a decrease in levels of the cyclin inhibitor p21. Moreover, we observed that RUNX2 silencing protected hMSCs from TNF-a's antiproliferative and apoptotic effects. This protection was accompanied by the inhibition of caspase-3 activity and Bax expression. Our results confirmed that RUNX2 is a critical link between cell fate, proliferation, and growth control. This study also suggested that, depending on the osteoblasts' differentiation stage, RUNX2 may control cell growth by regulating the expression of elements involved in hormone and cytokine sensitivity. ß

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“…18 However, compelling data highlight a proapoptotic role for NF-kB. Indeed, induction of apoptosis has been correlated to NF-kB activation in a wide variety of systems including fibroblasts, 26,27 T cells, 28,29 ceramide-activated osteoblasts 30 and dopaminergic neurons derived from Parkinson's disease patients. 31 Cell fate towards apoptosis or survival after NF-kB activation seems to be cell type specific and/or dependent on cell environment.…”

Section: Discussionmentioning

confidence: 99%

Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

et al. 2006

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Somatostatin is a multifunctional hormone that modulates cell proliferation, differentiation and apoptosis. Mechanisms for somatostatin-induced apoptosis are at present mostly unsolved. Therefore, we investigated whether somatostatin receptor subtype 2 (sst2) induces apoptosis in the nontransformed murine fibroblastic NIH3T3 cells. Somatostatin receptor subtype 2 expression induced an executioner caspase-mediated apoptosis through a tyrosine phosphatase SHP-1 (Src homology domain phosphatase-1)-dependent stimulation of nuclear factor kappa B (NF-jB) activity and subsequent inhibition of the mitogenactivated protein kinase JNK. Tumor necrosis factor a (TNFa) stimulated both NF-jB and c-Jun NH2-terminal kinase (JNK) activities, which had opposite action on cell survival. Importantly, sst2 sensitized NIH3T3 cells to TNFa-induced apoptosis by (1) upregulating TNFa receptor protein expression, and sensitizing to TNFa-induced caspase-8 activation; (2) enhancing TNFamediated activation of NF-jB, resulting in JNK inhibition and subsequent executioner caspase activation and cell death. We have here unraveled a novel signaling mechanism for a G protein-coupled receptor, which directly triggers apoptosis and crosstalks with a death receptor to enhance death ligand-induced apoptosis. Somatostatin is a regulatory peptide which is mostly expressed in the central and peripheral nervous system, in the gastro-intestinal tract and in the pancreas. Somatostatin acts via a family of five G protein-coupled receptors (GPCR), somatostatin receptor subtypes 1-5 (sst1-sst5) that are variably expressed throughout numerous tissues ranging from the central nervous system to the endocrine and immune systems. 1 Somatostatin or its analogues promote growth inhibition of various normal and tumor cells, both in vitro and in vivo. Somatostatin affects cell growth indirectly by inhibiting either trophic or growth factor synthesis and/or secretion, or their respective intracellular pathways. Somatostatin antiproliferative action also results from a direct blockade of cell cycle and/or induction of apoptosis. 2 Whereas somatostatin effect on cell cycle arrest has been extensively studied, mechanisms for somatostatin-induced apoptosis and receptor subtype implication are only partially elucidated. Somatostatin has been shown to induce cell death in both normal and tumoral cell models 3-9 . Among the five somatostatin receptors, sst3 and sst2 have been found to play a critical role in somatostatin-induced apoptosis of normal and tumor cells, respectively. 3,5,10 Mechanisms for somatostatin apoptotic action were shown to rely on the mitochondrial pathway through activation either of sst2 or sst3. However, signaling pathways coupling sst2 receptor to apoptosis have been partially elucidated.We have previously demonstrated that expression of sst2 in the nontransformated murine fibroblastic NIH3T3 cells results in a cell growth inhibition, which was dependent on the activation of the tyrosine phosphatase Src homology domain phosphatase-1 (SHP-1). 11 sst2...

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Ceramide-induced nuclear translocation of NF-κB is a potential mediator of the apoptotic response to TNF-α in murine clonal osteoblasts

Cited by 121 publications

References 32 publications

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

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