Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c-FLIP

Wang, Jin; Lobito, Adrian A.; Shen, F W; Hornung, Felicita; Winoto, Astar; Lenardo, Michael J.

doi:10.1002/1521-4141(200001)30:1<155::aid-immu155>3.0.co;2-x

Cited by 121 publications

(90 citation statements)

References 32 publications

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“…Signals through the BCR protect B cells from CD95-induced apoptosis through both transcriptionally dependent and independent mechanisms [25,[41][42][43]. In our studies, we found that stimulating B cells through CD40 after BCR activation substantially increased the percentage of cells rescued from CD95-induced apoptosis.…”

Section: Discussionmentioning

confidence: 64%

Rapid CD40‐mediated rescue from CD95‐induced apoptosis requires TNFR‐associated factor‐6 and PI3K

Benson

Hostager²,

Bishop

2006

Eur J Immunol

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The activation molecule CD40 and the death receptor CD95/Fas play important roles in regulating B cells so that effective antimicrobial immunity occurs without autoimmunity. CD40 signaling increases CD95 expression, sensitizing cells to apoptosis, but sustained CD40 signals rescue B cells from CD95 killing. Here we describe a mechanism of early CD40-mediated rescue from CD95-induced apoptosis in B cells. Maximal rescue was achieved when CD40 signals were given within 1-2 h of initiating CD95 apoptosis. CD40 signaling did not block association of Fas-associated death domain-containing protein with CD95, but decreased CD95-induced activation of caspases 3 and 8. Rapid CD40 rescue did not require NF-jB activation and was independent of de novo protein synthesis, but was dependent upon active PI3 K. Signaling via a CD40 mutant that does not bind TNFR-associated factor (TRAF)1, TRAF2, and TRAF3 rescued B cells from CD95-induced apoptosis. TRAF1/2/3-independent rescue was confirmed in B cell lines made deficient in these TRAF molecules by gene targeting. In contrast, CD40 rescue was completely abrogated in TRAF6-deficient B cells, which showed reduced activation of Akt in response to CD40 engagement. These results reveal a new rapid mechanism to balance B cell activation and apoptosis. IntroductionB cells integrate many signals that direct proliferation and differentiation into Ig-secreting plasma cells or longlived memory cells. Ultimately, activated B cells can be eliminated through apoptosis, which is important for maintaining immune tolerance and homeostasis [1,2]. Molecules of the TNFR family play critical roles in regulating the balance between B cell activation and apoptosis. CD40 signals allow B cells to proliferate, differentiate, switch isotype, form GC, and become memory cells [3][4][5]. CD40 stimulation also induces upregulation of other members of the TNFR family, including the death receptor CD95/Fas [6].The importance of CD95 in maintaining lymphocyte homeostasis and tolerance is highlighted by the human disease autoimmune lymphoproliferative syndrome (ALPS), caused by mutations in the CD95 signaling pathway [7,8] autoantibodies are produced, and systemic autoimmunity develops [9]. Expression of the CD95 transgene exclusively in T cells of lpr/lpr mice is sufficient to decrease lymphadenopathy, splenomegaly, and the accumulation of abnormal T cells, but these mice still produce autoantibodies, causing deposition of immune complexes in kidney glomeruli [10]. In contrast, expression of the CD95 transgene in both B and T cells reduces the levels of serum Ig, autoimmune symptoms, and mortality [11]. Thus, CD95 signaling in B cells is crucial for maintaining peripheral tolerance and preventing autoimmunity. When CD95 is oligomerized, either by binding to its ligand on T cells (CD95L) or by Ab against its extracellular domain, it recruits the adaptor molecule Fas-associated death domain-containing protein (FADD) and procaspase 8 into a complex called the deathinducing signaling complex (DISC) that cleaves pro...

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Section: Discussionmentioning

confidence: 64%

Rapid CD40‐mediated rescue from CD95‐induced apoptosis requires TNFR‐associated factor‐6 and PI3K

Benson

Hostager²,

Bishop

2006

Eur J Immunol

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“…Flip has been shown to be vital for the survival of hematopoeitic cells following differentiation and/or activation. Flip is up-regulated in B cells following BCR ligation [22], in T cells upon activation [23] and during dendritic and macrophage differentiation [10,24]. Here, we demonstrated that the pro-inflammatory molecules LPS and TNF- § induced Flip expression in monocytes which was associated with increased survival and retention of the zymogen isoform of caspase 8 and the full-length Bid.…”

Section: Discussionmentioning

confidence: 78%

“…PI3K regulates multiple pathways monocyte activity [11,[15][16][17][18][19][20][21][22][23][24][25][26][27]. PI3K is necessary for monocyte survival, since inhibition of PI3K and subsequently Akt resulted in cell death even in the presence of LPS or TNF- § .…”

Section: Discussionmentioning

confidence: 99%

The Fas-FasL death receptor and PI3K pathways independently regulate monocyte homeostasis

et al. 2001

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“…Our early Northern blot experiments suggested that some FLIP expression was induced by anti-Ig treatment of CD40L-stimulated B cells, but the data were inconclusive owing to the very low level of FLIP expression detected. However, definitive results were subsequently obtained by RT-PCR, which showed that FLIP RNA expression was induced within an hour of adding anti-Ig to CD40L-stimulated B cells, and that FLIP protein expression was upregulated within 6 h. These results were recently extended by reports indicating that FLIP overexpression interferes with Fasmediated apoptosis in primary B cells and in B cell lines [80], [81]. These studies together strongly suggest that FLIP is involved in bringing about sIg-induced resistance to Fas-mediated apoptosis because the two criteria discussed above were met, as described earlier for Bcl-xL: FLIP expression was upregulated coordinately with induction of Fas-resistance by anti-Ig, and isolated FLIP overexpression diminished B cell susceptibility to Fas signaling for cell death.…”

Section: Two Terminal Effectors Of Fas-resistance: Bcl-xl and Flipmentioning

confidence: 88%

Inducible resistance to Fas-mediated apoptosis in B cells

Rothstein

2000

Cell Res

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Apoptosis produced in B cells through Fas (APO-1, CD95) triggering is regulated by signals derived from other surface receptors: CD40 engagement produces upregulation of Fas expression and marked susceptibility to Fas-induced cell death, whereas antigen receptor engagement, or IL-4R engagement, inhibits Fas killing and in so doing induces a state of Fas-resistance, even in otherwise sensitive, CD40-stimulated targets. Surface immunoglobulin and IL-4R utilize at least partially distinct pathways to produce Fas-resistance that differentially depend on PKC and STAT6, respectively. Further, surface immunoglobulin signaling for inducible Fas-resistance bypasses Btk, requires NF-κB, and entails new macromolecular synthesis. Terminal effectors of B cell Fas-resistance include the known anti-apoptotic gene products, Bcl-xL and FLIP, and a novel anti-apoptotic gene that encodes FAIM (Fas Apoptosis Inhibitory Molecule). faim was identified by differential display and exists in two alter-

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Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c-FLIP

Cited by 121 publications

References 32 publications

Rapid CD40‐mediated rescue from CD95‐induced apoptosis requires TNFR‐associated factor‐6 and PI3K

Rapid CD40‐mediated rescue from CD95‐induced apoptosis requires TNFR‐associated factor‐6 and PI3K

The Fas-FasL death receptor and PI3K pathways independently regulate monocyte homeostasis

Inducible resistance to Fas-mediated apoptosis in B cells

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