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.

A20 Protects From CD40-CD40 Ligand-Mediated Endothelial Cell Activation and Apoptosis

“…21 Overexpression of A20 protected HCAECs from CD40-mediated apoptosis. This agrees with previous data by Hess et al 20 demonstrating that A20 protects the fibroblast SV80 cell line against apoptotic cell death induced by TNF. Protection from CD40-mediated apoptosis by A20 could relate to blockade of apoptotic pathways and caspase activation (as shown for TNF and Fas) 22 and/or a decrease in cytokine-induced surface expression of CD40.…”

“…To the extent that CD40 cross-linking upregulates A20 in a NF-Bdependent manner, one could easily speculate that A20 is part of a regulatory feedback loop modulating signaling through CD40. 19,20 We demonstrate that CD40-mediated signaling of cytokineactivated HCAECs leads to apoptosis contrasting with data in HUVECs. 21 Overexpression of A20 protected HCAECs from CD40-mediated apoptosis.…”

Impact of Interleukin-13 Responsiveness on the Synthetic and Proliferative Properties of Th1- and Th2-Type Pulmonary Granuloma Fibroblasts

“…Further investigation is underway to explore this resistance in greater detail, and we will be focusing on two anti-apoptotic factors that are strongly or selectively induced by IL13-PE in Th2-type fibroblasts: APRIL 62 and CD40. 63 APRIL confers protection from TRAIL-induced apoptosis whereas CD40 confers protection from tumor necrosis factor-␣-and Fas-induced apoptosis. 63,64 Our previous studies of untreated Th2-type fibroblasts have revealed that the surface expression of CD40 is 100-fold higher on these cells compared with that expressed on normal and Th1-type fibroblasts (unpublished data).…”

A functional CD40 receptor is expressed in pancreatic beta cells

“…The effects of CD40 signalling in non-immune cell types are not fully understood. However, several reports indicate that signalling through the CD40 receptor can induce survival [25,26] or growth inhibition and enhances apoptosis of various non-immune cell types [27,28].…”