CpG-Oligodeoxynucleotide Inhibits Smad-Dependent Bone Morphogenetic Protein Signaling: Effects on Myeloma Cell Apoptosis and In Vitro Osteoblastogenesis

Nørgaard, Nikolai N.; Holien, Toril; Jönsson, Sofia; Hella, Hanne; Espevik, Terje; Sundan, Anders; Standal, Therese

doi:10.4049/jimmunol.0903605

Cited by 19 publications

(15 citation statements)

References 54 publications

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“…Cells pretreated with chloroquine at concentrations of 25 mM failed to significantly reverse CpG-induced protection (Fig. 11B), suggesting that CpG, under our experimental conditions, may exert its effects through TLR9-independent mechanisms (48)(49)(50)(51). In support of this, we found that stimulation with non-TLR9-activating GpC control ODNs prior to Vpr(52-96) treatment was equally capable of inhibiting Vpr(52-96)-induced apoptosis (Fig.…”

Section: Cpg-induced C-iap-2 Expression and Protection From Vpr(52-96supporting

confidence: 75%

“…The precise mechanism by which CpG exerts its effects via TLR9-independent pathways is not well understood. Several TLR9-independent CpG signaling cascades have been suggested, including activation of two Src family kinases, Hck and Lyn (51), activation of transcription factor IFN regulatory factor-3 and IFN-b promoter stimulator-1 through the signaling pathway requiring the kinases TANK-binding kinase-1 and inducible kB kinase-i (60), DNAdependent protein kinase-induced Akt activation in murine macrophages (61), and inhibition of Smad protein-regulated signaling in human osteoblasts (48).…”

Section: Discussionmentioning

confidence: 99%

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CpG Protects Human Monocytic Cells against HIV-Vpr–Induced Apoptosis by Cellular Inhibitor of Apoptosis-2 through the Calcium-Activated JNK Pathway in a TLR9-Independent Manner

Saxena

Busca

Pandey

et al. 2011

The Journal of Immunology

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Monocytic cells survive HIV replication and consequent cytopathic effects because of their decreased sensitivity to HIV-induced apoptosis. However, the mechanism underlying this resistance to apoptosis remains poorly understood. Lymphocytic cells are exposed to microbial products because of their translocation from the gut in persons with chronic HIV infections or following coinfections. We hypothesized that activation of monocytic cells by such microbial products through interaction with corresponding TLRs may confer antiapoptotic signals. Using HIV-viral protein R (Vpr)(52–96) peptide as a model apoptosis-inducing agent, we demonstrated that unlike monocyte-derived macrophages, undifferentiated primary human monocytes and promonocytic THP-1 cells are highly susceptible to Vpr(52–96)-induced apoptosis. Interestingly, monocytes and THP-1 cells stimulated with TLR9 agonist CpG induced almost complete resistance to Vpr(52–96)-induced apoptosis, albeit through a TLR9-independent signaling pathway. Moreover, CpG selectively induced the antiapoptotic cellular inhibitor of apoptosis (c-IAP)-2 protein and inhibition of the c-IAP-2 gene by either specific small interfering RNA or synthetic second mitochondrial activator of caspases mimetic reversed CpG-induced resistance against Vpr(52–96)-mediated apoptosis. We demonstrated that c-IAP-2 is regulated by the JNK and calcium signaling pathway, in particular calmodulin-dependent protein kinase-II. Furthermore, inhibition of JNK and the calcium signaling including the calmodulin-dependent protein kinase-II by either pharmacological inhibitors or their specific small interfering RNAs reversed CpG-induced protection against Vpr(52–96)-mediated apoptosis. We also show that CpG induced JNK phosphorylation through activation of the calcium signaling pathway. Taken together, our results suggest that CpG-induced protection may be mediated by c-IAP-2 through the calcium-activated JNK pathway via what appeared to be TLR9-independent signaling pathways.

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Section: Cpg-induced C-iap-2 Expression and Protection From Vpr(52-96supporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

CpG Protects Human Monocytic Cells against HIV-Vpr–Induced Apoptosis by Cellular Inhibitor of Apoptosis-2 through the Calcium-Activated JNK Pathway in a TLR9-Independent Manner

Saxena

Busca

Pandey

et al. 2011

The Journal of Immunology

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“…35 Furthermore, TGF-b has been shown to induce apoptosis through a TAK1/TRAF6/ p38-dependent mechanism in prostate cancer cells. 36 However, in our hands, neither siRNA-mediated downregulation of p53, nor incubation of cells with pharmacological inhibitors of p38 or JNK, affected the ability of BMPs to induce apoptosis in myeloma cell lines 37 (data not shown). Interestingly, it takes significant time before the first apoptotic markers can be detected after BMP is added to myeloma cells in vitro.…”

Section: Discussionmentioning

confidence: 72%

Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC

et al. 2011

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Bone morphogenetic proteins (BMPs) have been shown to induce apoptosis and growth arrest in myeloma cells. However, the molecular mechanisms behind these events are not known. The MYC oncogene is a master regulator of cell growth and protein synthesis and MYC overexpression has been proposed to be associated with the progression of multiple myeloma. Here, we show that BMP-induced apoptosis in myeloma cells is dependent on downregulation of MYC. Moreover, the results suggest that targeting the MYC addiction in multiple myeloma is an efficient way of killing a majority of primary myeloma clones. We also found that myeloma cells harboring immunoglobulin (IG)-MYC translocations evaded BMP-induced apoptosis, suggesting a novel way for myeloma cells to overcome potential tumor suppression by BMPs.

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“…Chondrogenic differentiation of human BM-MSCs has not been reported to be altered by activation through LPS, PolyIC, or R848 (Liotta et al, 2008), but was increased by TLR2 activation on human UCB-MSCs (Kim et al, 2010). The osteogenic differentiation seems to be enhanced in human BM-MSCs, AD-MSCs, and UCB-MSCs after LPS, PGN, or Poly IC activation (Hwa Cho et al, 2006; Mo et al, 2008; Lombardo et al, 2009; Kim et al, 2010), while CpG oligodeoxynucleotides (CpG ODN), have been reported to inhibit it on human AD-MSCs and BM-MSCs (Hwa Cho et al, 2006; Pevsner-Fischer et al, 2007; Liotta et al, 2008; Lombardo et al, 2009; Nørgaard et al, 2010). It has been reported recently that TNFα and TLRs activate osteogenic differentiation of AD-MSC via upregulation of transcriptional coactivator with PDZ-binding motif (TAZ; Hwa Cho et al, 2010).…”

Section: Modulation Of Mscs Through Tlrsmentioning

confidence: 99%

Toll-Like Receptors as Modulators of Mesenchymal Stem Cells

DelaRosa¹,

Dalemans²,

Lombardo³

2012

Front. Immun.

169

166

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Mesenchymal stem cells (MSCs) have differentiation and immunomodulatory properties that make them interesting tools for the treatment of degenerative disorders, allograft rejection, or inflammatory and autoimmune diseases. Biological properties of MSCs can be modulated by the inflammatory microenvironment they face at the sites of injury or inflammation. Indeed, MSCs do not constitutively exert their immunomodulating properties but have to be primed by inflammatory mediators released from immune cells and inflamed tissue. A polarization process, mediated by Toll-like receptors (TLRs), toward either an anti-inflammatory or a pro-inflammatory phenotype has been described for MSCs. TLRs have been linked to allograft rejection and the perpetuation of chronic inflammatory diseases (e.g., Crohn’s disease, rheumatoid arthritis) through the recognition of conserved pathogen-derived components or endogenous ligands (danger signals) produced upon injury. Interest in understanding the effects of TLR activation on MSCs has greatly increased in the last few years since MSCs will likely encounter TLR ligands at sites of injury, and it has been proven that the activation of TLRs in MSCs can modulate their function and therapeutic effect.

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CpG-Oligodeoxynucleotide Inhibits Smad-Dependent Bone Morphogenetic Protein Signaling: Effects on Myeloma Cell Apoptosis and In Vitro Osteoblastogenesis

Abstract: Material Supplementary 5.DC1http://www.jimmunol.org/content/suppl/2010/08/09/jimmunol.090360References http://www.jimmunol.org/content/185/6/3131.full#ref-list-1

Cited by 19 publications

References 54 publications

CpG Protects Human Monocytic Cells against HIV-Vpr–Induced Apoptosis by Cellular Inhibitor of Apoptosis-2 through the Calcium-Activated JNK Pathway in a TLR9-Independent Manner

CpG Protects Human Monocytic Cells against HIV-Vpr–Induced Apoptosis by Cellular Inhibitor of Apoptosis-2 through the Calcium-Activated JNK Pathway in a TLR9-Independent Manner

Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC

Toll-Like Receptors as Modulators of Mesenchymal Stem Cells

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