CD40 induces resistance to TNF-mediated apoptosis in a fibroblast cell line

Abstract

CD40, a member of the TNF receptor family, has been characterized as an important T-B cell interaction molecule. In B cells it co-stimulates isotype switching, proliferation, adhesion and is involved in cell death regulation. In addition to B cells, CD40 expression was found on transformed cells and carcinomas. However, little is known about its functions in these cell types. Recent studies show that CD40 mediates the production of pro-inflammatory cyto-kines in non-hematopoietic cells, inhibits proliferation or induces cell death. In some cell types the apoptotic program triggered by CD40 is only executed when protein synthesis is blocked, suggesting the existence of constitutively expressed resistance proteins. Here we demonstrate that CD40, similar to the 55-kDa TNF receptor (p55TNFR), has a dual role in the regulation of apoptosis in such cells. In the fibroblast cell line SV80 both CD40 and the p55TNFR trigger apoptosis when protein synthesis is blocked with cycloheximide (CHX). Simultaneous activation of both receptors results in markedly enhanced cell death. However , CD40 activation more than 4 h prior to a challenge with TNF/CHX paradoxically conferred resistance to TNF-induced cell death. Protection correlated with NF-O B induction and up-regulation of the anti-apoptotic zinc finger protein A20. Overexpression of A20 in turn rendered SV80 cells resistant to TNF cytotoxicity. In conclusion, our data provide evidence that CD40 may regulate cell death in non-hematopoietic cells in a dual fashion: the decision upon apoptosis or survival of a CD40-activated cell seems to depend on its ability to up-regulate resistance factors.

Transgenic expression of the human A20 gene in cloned pigs provides protection against apoptotic and inflammatory stimuli

“…It is known that A20‐mediated inhibition of apoptosis in vitro does not protect all cell lines studied. Human breast carcinoma MCF7 cells, murine fibrosarcoma WEHI164 cells, murine embryonic fibroblast NIH3T3 cells, and human umbilical vein endothelial cells are protected against TNF cytotoxicity, but not human cervix carcinoma HeLa cells, lung epithelial A549 cells, or human hepatoma HepG2 cells [6,51–56]. The reason why some cell lines are protected by A20 and others not, is still unclear [57].…”

Possible Role of Natural Immune Response against Altered Fibroblasts in the Development of Post‐Operative Adhesions

“…Fibroblast cytokine expression is regulated through CD40 function and CD40–CD40 ligand system may play a stimulatory role in fibrogenesis 15,16 . However, simultaneous activation of CD40 and TNF receptor resulted in enhanced cell death in fibroblasts 17 …”

Cell death induction by receptors of the TNF family: towards a molecular understanding

“…Growing evidence indicates, however, that such effects can also be triggered by other receptors of the family. These include the two other TNF receptors known: TNF‐R75 (CD120b), whose cytotoxic signalling [21, 22]reportedly plays an important role in the self‐destruction of activated CD8 lymphocytes (more so than that of TNF‐R55) [23], and the LT‐β receptor (which binds the complex formed between LT‐α and LT‐β) [24], and also DR3/WSL‐1/TRAMP (a receptor closely related to TNF‐R55) [9–11], the low‐affinity NGF receptor [25, 26], CD40 [27, 28], and others. In this review we discuss the cytotoxicity induced by TNF‐R55 and Fas/Apo‐1, as these are the only receptors whose cytocidal function is at least partially understood at the molecular level.…”