Aged mice exhibit distinct peripheral B‐cell phenotypes differing in apoptotic susceptibility: An ex vivo analysis

Verdier, Mireille; Malissein, Emilie; E, Munteanu; Jayat-Vignoles, Chantal; Ratinaud, Marie‐Hélène; Troutaud, Danielle

doi:10.1002/cyto.a.20310

Cited by 3 publications

(4 citation statements)

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“…As expected, apoptosis induced by rituximab was observed in both cell lines and associated with an inhibition of the constitutively activated PI3K-Akt signaling pathway, known to lead to chemosensitization [5], [37]. Furthermore, we confirmed the higher apoptotic sensitivity of SUDHL6 [26]. Such differential sensitivity to apoptosis may be explained by the lower constitutively expression of P-Akt detected in SUDHL6 cells as compared to SUDHL4, in accordance to previous observations for other DLBCL cell lines [5].…”

Section: Discussionsupporting

confidence: 92%

“…Several tumor-associated and host-associated mechanisms have been proposed, including mutations or poor surface CD20 antigen expression and, more recently, polymorphisms in FcγRIIIA receptor [36]. To further assess the role of NT production in rituximab sensitivity, we exposed cells to rituximab, as the two studied SUDHL cell lines have been reported to have differential apoptotic sensitivity in response to rituximab [26]. As expected, apoptosis induced by rituximab was observed in both cell lines and associated with an inhibition of the constitutively activated PI3K-Akt signaling pathway, known to lead to chemosensitization [5], [37].…”

Section: Discussionmentioning

confidence: 99%

“…DNA fragmentation was detected by flow cytometric analysis after propidium iodide staining as previously described [26] and using a FACSVantage DIVA SE flow cytometer. Percentage of apoptotic cells was then defined as the percentage of cells with DNA staining before G0/G1 peak (hypodiploid, sub-G1 peak).…”

Section: Methodsmentioning

confidence: 99%

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Endogenous Neurotrophins and Trk Signaling in Diffuse Large B Cell Lymphoma Cell Lines Are Involved in Sensitivity to Rituximab-Induced Apoptosis

et al. 2011

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BackgroundDiffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. Immunochemotherapy, a combination of rituximab to standard chemotherapy, has resulted in improved survival. However a substantial proportion of patients still fail to reach sustained remission. We have previously demonstrated that autocrine brain-derived neurotrophic factor (BDNF) production plays a function in human B cell survival, at least partly via sortilin expression. As neurotrophin receptor (Trks) signaling involved activation of survival pathways that are inhibited by rituximab, we speculated that neurotrophins may provide additional support for tumour cell survival and therapeutic resistance in DLBCL.Methodology/Principal FindingsIn the present study, we used two DLBCL cell lines, SUDHL4 and SUDHL6, known to be respectively less and more sensitive to rituximab. We found by RT-PCR, western blotting, cytometry and confocal microscopy that both cell lines expressed, in normal culture conditions, BDNF and to a lesser extent NGF, as well as truncated TrkB and p75NTR/sortilin death neurotrophin receptors. Furthermore, BDNF secretion was detected in cell supernatants. NGF and BDNF production and Trk receptor expression, including TrkA, are regulated by apoptotic conditions (serum deprivation or rituximab exposure). Indeed, we show for the first time that rituximab exposure of DLBCL cell lines induces NGF secretion and that differences in rituximab sensitivity are associated with differential expression patterns of neurotrophins and their receptors (TrkA). Finally, these cells are sensitive to the Trk-inhibitor, K252a, as shown by the induction of apoptosis. Furthermore, K252a exhibits additive cytotoxic effects with rituximab.Conclusions/SignificanceCollectively, these data strongly suggest that a neurotrophin axis, such NGF/TrkA pathway, may contribute to malignant cell survival and rituximab resistance in DLBCL.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Endogenous Neurotrophins and Trk Signaling in Diffuse Large B Cell Lymphoma Cell Lines Are Involved in Sensitivity to Rituximab-Induced Apoptosis

et al. 2011

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“…Each analysis was done on at least 10,000 cells gated in the region of the cells on the basis of light scatter properties. Fluorescence data were displayed on four-decade log scales [30].…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

Anti-Bcl-2 family members, zfBcl-xL and zfMcl-1a, prevent cytochrome c release from cells undergoing betanodavirus-induced secondary necrotic cell death

Chen

et al. 2007

Apoptosis

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Nervous necrosis virus (NNV)-induced, host cell apoptosis mediates secondary necrosis by an ill-understood process. In this study, redspotted grouper nervous necrosis virus (RGNNV) is shown to induce mitochondria-mediated necrotic cell death in GL-av cells (fish cells) via cytochrome c release, and anti-apoptotic proteins are shown to protect these cells from death. Western blots revealed that cytochrome c release coincided with disruption of mitochondrial ultrastructure and preceded necrosis, but did not correlate with caspases activation. To identify the mediator(s) of this necrotic process, a protein synthesis inhibitor (cycloheximide; CHX; 0.33 microg/ml) was used to block cytochrome c release as well as PS exposure and mitochondrial membrane permeability transition pore (MMP) loss. CHX (0.33 microg/ml) completely blocked viral protein B2 expression, and partly blocked protein A, protein alpha, and a pro-apoptotic death protein (Bad) expression. Overexpression of B2 gene increased necrotic-like cell death up to 30% at 48 h post-transfection, suggesting that newly synthesized protein (B2) may be involved in this necrotic process. Finally, necrotic death was prevented by overexpression of Bcl-2 family proteins, zfBcl-x(L) and xfMcl-1a. Thus, new protein synthesis and release of cytochrome c are required for RGNNV-induced necrotic cell death, which can be blocked by anti-apoptotic Bcl-2 members.

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Deoxynivalenol alters circulating and splenic leukocytes and cell migration markers in interaction with time course and sex in young and old BALB/c mice

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Deoxynivalenol (DON), produced by Fusarium graminearum and Fusarium culmorum, is commonly found in wheat, corn, oats and barley. We hypothesize DON exposure could change leukocyte subset number and their migration potential in peripheral blood with interaction of age and sex, which could be sensitive biomarkers to predict DON exposure for human epidemiological screening. The first mouse study was done in 6-7 week old BALB/c mice. Peripheral blood (PB) and splenic leukocytes were stained and detected by flow cytometry. The results showed the percentage of B cells (CD19 +) in PB was reduced in both sexes at 1.0 and 2.0 ppm at 14 d, with no reduction of B cells after 28 d. Monocytes (CD11b +) in PB and macrophage cells (CD11b +) in spleen were decreased in female BALB/c mice at 1.0 and 2.0 ppm after 28 d, which suggested sex hormones interacted with DON immunotoxicity. No toxicity was observed at doses 0.5 ppm or less. The second mouse study was done in 2-3 month old and 16 month old BALB/c mice. Granulocytes in both ages and sexes were increased at 1.0 and 2.0 ppm DON at 14 d, but normalized after 28 d. Percentage of T helper cells in PB was decreased in young female mice fed 2.0 ppm DON after 14 d, not after 28 d. Percentage of CXCR5 + B cells was decreased in old female mice fed 2.0 ppm DON after 14 d, but not after 28 d. CD29 + CD11a + neutrophils were increased at 1.0 and 2.0 ppm DON in old male mice after 14 d, but no difference was observed after 28 d. CCR9 + T cytotoxic cells were increased in old male mice fed 2.0 ppm DON after 28 d. Taken together, these results suggested DON inhibited T helper cells in young female mice and interrupted B cell, neutrophil and T cytotoxic cell migration potentials in old mice. Most DON toxicity was transient, and interacted with age and sex. In conclusion, the surface markers of leukocytes in PB were changed in BALB/c mice fed 1.0 ppm and 2.0 ppm DON. Age and sex interacted with DON exposure. Most of the effects of DON were temporary, which suggested BALB/c mice adapted to DON exposure. CHAPTER GENERAL INTRODUCTION Research questions Immune system and intestine are the two main targets after DON exposure. Few studies reported the effects of subchronic low doses of DON, which simulated real human exposures in comparison with advisory guidelines for DON ranging from 0.5-2 ppm across the EU, Canada, China and US (Landgren 2005). In our lab, a previous study found 1.0 ppm DON plus 0.9 ppm 3-Ac DON and 2.0 ppm DON plus 1.8 ppm 3-Ac DON inhibited peripheral blood lymphocytes in male BALB/c mice after 28 d (Landgren 2005), which suggested peripheral blood leukocytes could be sensitive biomarker to predict low dose of DON exposure in human epidemiological study. The current mouse studies were to find sensitive biomarkers in peripheral blood to predict low dose of immunotoxicity of DON. General markers used in order to determine if DON inhibits T helper, T cytotoxic, B, monocytes and neutrophils were CD4, CD8, CD19, CD11b, and CD11b + (granulocytes), respectively. CD11b is also a ma...

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Aged mice exhibit distinct peripheral B‐cell phenotypes differing in apoptotic susceptibility: An ex vivo analysis

Cited by 3 publications

References 48 publications

Endogenous Neurotrophins and Trk Signaling in Diffuse Large B Cell Lymphoma Cell Lines Are Involved in Sensitivity to Rituximab-Induced Apoptosis

Endogenous Neurotrophins and Trk Signaling in Diffuse Large B Cell Lymphoma Cell Lines Are Involved in Sensitivity to Rituximab-Induced Apoptosis

Anti-Bcl-2 family members, zfBcl-xL and zfMcl-1a, prevent cytochrome c release from cells undergoing betanodavirus-induced secondary necrotic cell death

Deoxynivalenol alters circulating and splenic leukocytes and cell migration markers in interaction with time course and sex in young and old BALB/c mice

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