Opposing Effects of Transmembrane and Soluble FAS Ligand Expression on Inflammation and Tumor Cell Survival

Abstract

Fas ligand (FasL) has been shown to mediate both apoptotic and inflammatory reactions. To rigorously assess the physiological role of different forms of the FasL molecule with regard to these two distinct processes, we isolated stably transfected lymphoma cell lines that expressed either murine wild-type FasL, membrane-only FasL, or functionally distinct forms of soluble FasL. First, the ability of these lines to induce an inflammatory response was assessed in vivo by injecting the transfectants intraperitoneally and measuring subsequent neutrophil extravasation into the peritoneal cavity. Second, lines were assessed by injecting the transfectants subcutaneously and monitoring their growth as solid tumors. Our study clearly demonstrated that the extent of inflammation induced by the transfectants directly correlated with their relative cytotoxic activities. A neutrophil response could only be elicited in mice with intact Fas death domains although Fas expression by the neutrophils was not essential. Lymphoma cells expressing the soluble FasL form corresponding to the natural cleavage product could not trigger apoptosis and did not induce a neutrophil response. In contrast to the other FasL transfectants, these cells survived as tumor transplants. However, expression of soluble FasL was not benign, but actually suppressed the inflammatory response and protected other transfectants from the effector mechanisms elicted by membrane-bound FasL.

The effects of FasL on inflammation and tumor survival are dependent on its expression levels

“…Consistent with previous reports, [13][14][15][16] we found a massive neutrophil infiltration in the FasL high tumor (Figure 4). FasL med tumor induced a moderate inflammation, in agreement with their reduced growth rate compared with the parental tumors.…”

“…23 A recent study provided evidence that FasL-triggered inflammation correlated with its cytotoxic activity and was in fact a secondary effect of the locally induced apoptosis. 16 Accordingly, the induction of inflammation may depend not only on the level of FasL on tumors but also on the FasL susceptibility of the surrounding tissues. It is possible that certain human tumors may express high levels of FasL to counterattack the immune effector cells without inducing an inflammatory response if their adjacent tissues are resistant to Fasmediated apoptosis.…”

“…11,12 In contrast to these observations, tumor cells engineered to express exogenous FasL triggered a potent neutrophil-mediated local inflammatory response and were rapidly rejected. [13][14][15][16] These conflicting findings have led to extensive debates on the role of FasL in immune privilege versus inflammation. 11,12,17,18 It has been proposed that the effect of FasL may depend on its expression level 12 this hypothesis needs further evidences.…”

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

“…These results indicate that membranebound FasL can more effectively induce apoptosis in Fasexpressing cells than soluble FasL. 24 Recently, it has been reported that the TRAIL-mediated killing pathway on immune cells also plays an important role in elimination of tumor cells. 25 We tested whether soluble TRAIL would induce apoptotic cell death of parental D122 and cytokine transfectants.…”

The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia

“…For instance, MMP-7 is capable of cleaving Fas ligand (FasL), resulting in soluble FasL (sFasL). This sFasL can then bind to Fas receptor on tumor cells and the complex is rapidly internalized, resulting in down regulation of Fas-receptor [148].…”