IL-4 inhibits apoptosis and prevents mitochondrial damage without inducing the switch to necrosis observed with caspase inhibitors

Lemaire, Christophe; Andréau, Karine; Fraisse, Carole Sidoti-de; Adam, Arlette; Souvannavong, Vongthip

doi:10.1038/sj.cdd.4400556

Cited by 22 publications

(18 citation statements)

References 22 publications

(29 reference statements)

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“…Previous findings have shown that IL-4 has antiapoptotic activity by countering early mitochondrial perturbations (27). However, in the present study, the effects of LPS on the maintenance of the ⌬⌿m occurred later than those observed for IL-4 (at 15 versus 8 h).…”

Section: Discussioncontrasting

confidence: 55%

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Lipopolysaccharide Protects Primary B Lymphocytes from Apoptosis by Preventing Mitochondrial Dysfunction and Bax Translocation to Mitochondria

2004

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Mature B lymphocytes undergo apoptosis when they are cultured in the absence of survival factors. Gramnegative bacterial lipopolysaccharide (LPS) prevents this spontaneous apoptosis. This study aimed to better define the signaling pathway(s) involved in the antiapoptotic activity of this endotoxin. We report here that, in addition to its effects on spontaneous apoptosis, LPS protects B cells from apoptosis induced by the broad-spectrum protein kinase inhibitor staurosporine. LPS increased cell viability and concomitantly maintained the mitochondrial transmembrane potential (⌬⌿m) and high glutathione levels. Moreover, LPS inhibited cytosolic cytochrome c release and decreased caspase-9 activation. Unlike staurosporine, LPS induced the retention of Bax, a proapoptotic protein of the Bcl-2 family, in the cytosol by preventing its translocation to mitochondria. These results suggest that Bax relocalization from the cytosol to the mitochondria is an important step of mature B-cell apoptosis and that the antiapoptotic activity of LPS occurs upstream of mitochondrial events.

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Section: Discussioncontrasting

confidence: 55%

“…The ⌬⌿m, glutathione (GSH) levels, and cell viability were measured as previously described (27). The ⌬⌿m was determined by the retention of DiOC 6 (3), a cellpermeative cationic lipophilic fluorochrome which specifically accumulates in mitochondria as a function of their ⌬⌿m.…”

Section: Methodsmentioning

confidence: 99%

Lipopolysaccharide Protects Primary B Lymphocytes from Apoptosis by Preventing Mitochondrial Dysfunction and Bax Translocation to Mitochondria

2004

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“…LPS from Salmonella enterica serotype Minnesota Re 595 (Re mutant) and 6-diamidino Cell preparation and culture. Mature B lymphocytes were purified as previously described (25). Briefly, spleen cells were first treated with the anti-Thy-1.2 (CD90) monoclonal antibody at 4°C for 45 min, followed by incubation with Low-Tox rabbit complement at 37°C for 1 h, and then separated on a discontinuous Percoll gradient (GE Healthcare Bio-Sciences, Uppsala, Sweden).…”

Section: Methodsmentioning

confidence: 99%

Lipopolysaccharide fromSalmonella entericaActivates NF-κB through both Classical and Alternative Pathways in Primary B Lymphocytes

2007

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Lipopolysaccharides (LPS) are potent polyclonal B-lymphocyte activators. Recently, we have shown that LPS inhibits both spontaneous and drug-induced apoptosis in mature B lymphocytes, through cytosolic retention of Bax, a proapoptotic protein of the Bcl-2 family, by preventing its translocation to mitochondria. Research within the last few years has revealed that members of the NF-B transcription factor regulate cell viability by activating genes involved in mitochondrion-dependent apoptosis. In this report, we examined the effect of sustained LPS stimulation on cytosolic and nuclear proteins of the IB/NF-B family to determine which NF-B pathway, canonical (classical) or noncanonical (alternative), is activated by this agent in mature B cells. Immunoblotting analyses showed that LPS induced a time-dependent degradation of the NF-B inhibitors IB␤ and IB (preferentially to isoform IB␣), via IB kinase ␤. In addition, we observed that LPS triggered the processing of NF-B p105 to p50 and that of NF-B p100 to p52 in parallel with nuclear translocation of active p50 and p52, as NF-Bp50/RelA and NF-Bp52/RelB heterodimers, respectively. These results suggest that sustained stimulation with LPS can activate NF-B through both classical and alternative pathways.

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“…2 These signals (i.e. CD40 plus IL-4) also induce the expression of cell cycle regulatory proteins that facilitate both G1 cell cycle exit; 3 as well as rescue from apoptosis 4 in normal B cells.…”

Section: Introductionmentioning

confidence: 99%

Decoupling of normal CD40/interleukin-4 immunoglobulin heavy chain switch signal leads to genomic instability in SGH-MM5 and RPMI 8226 multiple myeloma cell lines

et al. 2006

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The processes mediating genomic instability and clonal evolution are obscure in multiple myeloma (MM). Acquisition of new chromosomal translocations into the switch region of the immunoglobulin heavy chain (IgH) gene (chromosome 14q32) in MM, often heralds transformation to more aggressive disease. Since the combined effects of CD40 plus interleukin-4 (IL-4) mediate IgH isotype class switch recombination (CSR), and this process involves DNA double strand break repair (DSBR), we hypothesized that CD40 and/or IL-4 activation of MM cells could induce abnormal DNA DSBR and lead to genomic instability and clonal evolution. In this study, we show that MM cell lines that are optimally triggered via CD40 and/or IL-4 demonstrate abnormal decoupling of IL-4 signal transduction from CD40. Specifically, CD40 alone was sufficient to trigger maximal growth of tumor cells. We further demonstrate that CD40 triggering induced both DNA DSBs as well as newly acquired karyotypic abnormalities in MM cell lines. Importantly, these observations were accompanied by induction of activation induced cytidine deaminase expression, but not gross apoptosis. These data support the role of abnormal CD40 signal transduction in mediating genomic instability, suggesting a role for the CD40 pathway and intermediates in myelomagenesis and clonal evolution in vivo.

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IL-4 inhibits apoptosis and prevents mitochondrial damage without inducing the switch to necrosis observed with caspase inhibitors

Cited by 22 publications

References 22 publications

Lipopolysaccharide Protects Primary B Lymphocytes from Apoptosis by Preventing Mitochondrial Dysfunction and Bax Translocation to Mitochondria

Lipopolysaccharide Protects Primary B Lymphocytes from Apoptosis by Preventing Mitochondrial Dysfunction and Bax Translocation to Mitochondria

Lipopolysaccharide fromSalmonella entericaActivates NF-κB through both Classical and Alternative Pathways in Primary B Lymphocytes

Decoupling of normal CD40/interleukin-4 immunoglobulin heavy chain switch signal leads to genomic instability in SGH-MM5 and RPMI 8226 multiple myeloma cell lines

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