| Fas ligand (FasL) is a cytokine from the tumor necrosis factor family that induces apoptosis in cells upon binding to the cell surface death receptor Fas (CD95/Apo1). This physiological cell elimination process is essential for proper functioning of the immune system, as it maintains the immune system homeostasis. Whereas FasL is primarily expressed on the surface of lymphoid cells, Fas is broadly expressed in numerous non-lymphoid tissues. During injury and inflammation infilatrated lymphocytes can induce Fas-mediated apoptosis of parenchymal cells in tissues and cause tissue injury. It is known that the adhesion of cells to the extracellular matrix protects from Fas-mediated apoptosis by inducing integrin-mediated prosurvival signaling. Here we show an unexpected finding that CCN1 (CYR61) and CCN2 (CTGF), the extracellular matrix proteins upregulated at sites of inflammation and wound repair, act via integrin alpha6beta1 and cell surface heparan sulfate proteoglycans to augment FasL-induced apoptosis. Mechanistically, CCN1 protein activates neutral sphingomyelinase, a ceramide-generating enzyme, to induce accumulation of reactive oxygen species (ROS) in cells, critical for the synergism with FasL. In the presence of FasL, CCN1-induced ROS causes hyperphosphorylation of p38 MAPK, which regulates recruitment of Bax to mitochondria to enhance cytochrome c release and apoptosis. Furthermore, Fas-dependent hepatic apoptosis induced by an agonistic monoclonal anti-Fas antibody or intragastric administration of alcohol is severely blunted in knockin mice expressing an apoptosis-defective Ccn1 allele. These results demonstrate that CCN1 is a physiologic regulator of Fas-mediated apoptosis, and that the ECM microenvironment can profoundly modulate Fas-dependent apoptosis through CCN1 expression. |
