Opposing effects of transmembrane and soluble Fas ligand expression on inflammation and tumor cell survival

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 isolat ed stably transfected lymphoma cell lines that expressed either murine wild -type FasL, membrane-only FasL, or functionally distinct forms of soluble F asL. First, the ability of these lines to induce an inflammatory response w as assessed in vivo by injecting the transfectants intraperitoneally and me asuring subsequent neutrophil extravasation into the peritoneal cavity. Sec ond, lines were assessed by injecting the transfectants subcutaneously and monitoring their growth as solid tumors. Our study clearly demonstrated tha t the extent of inflammation induced by the transfectants directly correlat ed with their relative cytotoxic activities. A neutrophil response could on ly be elicited in mice with intact Fas death domains although Fas expressio n by the neutrophils was not essential. Lymphoma cells expressing the solub le FasL iol-nl corresponding to the natural cleavage product could not trig ger apoptosis and did not induce a neutrophil response. In contrast to the other Fast transfectants. these cells survived as tumor transplants. Howeve r, expression of soluble FasL was not benign, but actually suppressed the i nflammatory response and protected other transfectants from the effector me chanisms elicted by membrane-bound FasL.