Fas Signal Transduction Triggers Either Proliferation or Apoptosis in Human Fibroblasts

Abstract

Although shown to be highly expressed by the epidermis in inflammatory skin disease, the ability of the Fas protein to trigger apoptosis in the distinct cell subpopulations of cutaneous tissue, particularly with regard to receptor density and the degree of crosslinking, has not been fully characterized. We therefore determined the effect of Fas cross-linking in primary human dermal fibroblasts at both high and low levels of Fas receptor expression. First, we examined the effects of the anti-Fas monoclonal antibody, CH-11, on fibroblasts expressing low basal levels of Fas. In these cells Fas aggregation stimulated proliferation by 160 +/- 10% over untreated controls. In contrast, the same concentration of CH-11 had an inhibitory effect on epidermal keratinocyte growth. Because Fas is upregulated in inflamed skin, we next examined the effects of Fas cross-linking on fibroblasts expressing augmented levels ofFas. Fibroblasts were either transfected with plasmids for overexpression of full length or bioengineered Fas receptors or were transduced with a retroviral Fas expression vector. In these cells Fas oligomerization triggered the morphologic changes indicative of apoptosis regardless of whether or not the Fas-signaling domain was tethered to the plasma membrane. These studies indicate that Fas oligomerization in dermal fibroblasts may initiate dual signaling programs, either proliferation or apoptosis, and that the chosen outcome may depend upon the magnitude of Fas aggregation.

Addressing the “Fas Counterattack” Controversy: Blocking Fas Ligand Expression Suppresses Tumor Immune Evasion of Colon CancerIn vivo

“…Recent studies have shown that Fas can transduce activation and proliferation signals although the mechanism by which this occurs is poorly understood (24,25). Because CMT93 cells coexpress Fas and FasL, tumor-expressed FasL may act in an autocrine or juxtacrine manner to promote tumor growth.…”

The Fas System Confers Protection against Alveolar Disruption in Hyperoxia-Exposed Newborn Mice

“…While seemingly paradoxical, this novel proliferative function of Fas/FasL signaling during alveolarization is consistent with an increasing body of evidence suggesting that Fas/FasL signaling has important nonapoptotic functions in addition to its better known apoptotic effects. Fas stimulation can enhance proliferation in lymphocytes, fibroblasts, hepatocytes, cardiomyocytes, and in tumor cells of many different tissue origins (49)(50)(51)(52)(53)(54)(55)(56)(57)(58). In addition to promoting proliferation and activation, Fas engagement can also trigger inflammatory changes, including the release of IL-6 and IL-8 (59, 60) and up-regulation of cell surface integrins (61).…”

Death Receptor-Ligand Systems in Cancer, Cell Death, and Inflammation

“…Shortly after the discovery of the CD95 system, first reports appeared that CD95 stimulation does not always induce apoptosis but can also stimulate proliferation (e.g., in CD3-activated T cells) (Alderson et al 1993(Alderson et al , 1994(Alderson et al , 1995Desbarats et al 1999;Kennedy et al 1999), fibroblasts (Freiberg et al 1997), and hepatocytes following partial hepatectomy (Desbarats and Newell 2000). Intriguingly, certain cancer cells also responded to CD95 stimulation by increasing their proliferation (OwenSchaub et al 1993) or their motility and invasiveness (Barnhart et al 2004).…”