Receptor‐specific regulation of B‐cell susceptibility to Fas‐mediated apoptosis and a novel Fas apoptosis inhibitory molecule

Abstract

The susceptibility of primary B cells to Fas (APO-1, CD95)-mediated apoptosis is modulated by signals derived from additional surface receptors: CD40 engagement produces upregulation of Fas expression and marked sensitivity to Fas-induced cell death, whereas antigen receptor engagement, or interleukin-4 receptor (IL-4R) engagement, inhibits Fas killing and thereby produces Fas resistance, even in otherwise susceptible, CD40-stimulated targets. Surface immunoglobulin (sIg) and IL-4R utilize distinct signaling pathways to produce Fas resistance that rely on protein kinase C and signal transducer and activator of transcription 6, respectively sIg signaling for inducible Fas resistance requires nuclear factor-kappaB and depends on new macromolecular synthesis. Proximate mediators for Fas resistance include the known anti-apoptotic gene products Bcl-xL and FLIP (but not Btk), and a novel anti-apoptotic gene that encodes Fas apoptosis inhibitory molecule (FAIM). FAIM was identified by differential display and was cloned as two alternatively spliced forms: FAIM-S is broadly expressed, whereas faim-L expression is tissue specific. faim is highly evolutionarily conserved, suggesting an important function throughout phylogeny. Inducible resistance to Fas-mediated apoptosis is speculated to protect antigen-specific B cells during potentially dangerous interactions with FasL-bearing T cells; the elevated sIg-signaling threshold for inducible Fas resistance in autoreactive, tolerant B cells would insure against autoimmunity. However, aberrant acquisition of Fas resistance may allow autoreactive B cells to escape Fas deletion and malignant lymphocytes to thwart antitumor immunity.

The death receptor antagonist FAIM promotes neurite outgrowth by a mechanism that depends on ERK and NF-κB signaling

“…Whereas overexpression of FAIM markedly enhances neurite growth from peripheral and central neurons and from the PC12 neuronal cell line, reduction of endogenous FAIM by RNAi significantly decreases NGF-stimulated neurite growth from PC12 cells and SCG neurons. Furthermore, in contrast to work showing the antiapoptotic function of FAIM in B-lymphocytes ( Schneider et al, 1999 ; Rothstein et al, 2000 ), we find that modulating FAIM expression has no effect on neuronal survival. Fas and Fas ligand (FasL) are widely expressed in the nervous system in both neurons and glial cells ( Park et al, 1998 ; Spanaus et al, 1998 ; Raoul et al, 1999 ; Casha et al, 2001 , Choi et al, 1999 ; Wohlleben et al, 2000 ; Desbarats et al, 2003 ).…”

“…Fas apoptosis inhibitory molecule (FAIM) is a Fas antagonist that was initially characterized by differential display as a gene that is up-regulated in B cells resistant to Fas-mediated cell death and functions as an inhibitor of Fas-induced cell death ( Schneider et al, 1999 ). FAIM is highly conserved in evolution from Caenorhabditis elegans to humans and is broadly expressed in many tissues ( Rothstein et al, 2000 ). Recently, an alternatively spliced isoform of FAIM, FAIM-L, has been identified, which is predominantly expressed in the brain ( Zhong et al, 2001 ).…”

Hetero-oligomerization between the TNF receptor superfamily members CD40, Fas and TRAILR2 modulate CD40 signalling

“…GC B cells express CD40 and Fas and undergo FasL-mediated apoptosis, unless a survival signal is provided by BCR or CD40 engagement. 38, 39, 40, 41 The same type of data does not exist for TRAILR2, but it was shown ex vivo on primary human B cells that BCR and/or CD40L signals can rescue naive B cells, but not memory B cells, from TRAIL-induced apoptosis. 13 Together, these data suggest that signals transduced by Fas, TRAILR2 and CD40 are entangled to finely control the fate of B cells.…”

Galectins in Chagas Disease: A Missing Link Between Trypanosoma cruzi Infection, Inflammation, and Tissue Damage

“…This elevated expression was also detected when resting B cells were activated in vitro with different stimuli, such as lipopolysaccharide and F(ab’)2 anti-μ and anti-CD40 antibodies, reaching a maximum effect after a long period of incubation. In both cases, galectin-3 was upregulated in the presence of IL-4, a cytokine that favored B cell survival and the generation of a memory phenotype ( Rothstein et al, 2000 ; Acosta Rodriguez et al, 2003 ). However, IL-4 activity was abolished when the synthesis of endogenous galectin-3 was interrupted, clearly demonstrating the existence of a mechanism of cross-talk between IL-4 and galectin-3 in the context of acute Chagas disease.…”