Cytotoxicity of TNFα is regulated by integrin-mediated matrix signaling

Cytokines of the tumor necrosis factor (TNF) family regulate inflammation and immunity, and a subset of this family can also induce cell death in a context-dependent manner. Although TNF alpha is cytotoxic to certain tumor cell lines, it induces apoptosis in normal cells only when NF kappa B signaling is blocked. Here we show that the matricellular protein CCN1/CYR61 can unmask the cytotoxic potential of TNF alpha without perturbation of NF kappa B signaling or de novo protein synthesis, leading to rapid apoptosis in the otherwise resistant primary human fibroblasts. CCN1 acts through binding to integrins alpha(v)beta(5), alpha(6)beta(1), and syndecan-4, triggering the generation of reactive oxygen species (ROS) through a Rac1-dependent mechanism via 5-lipoxygenase and the mitochondria, leading to the biphasic activation of JNK necessary for apoptosis. Mice with the genomic Ccn1 locus replaced with an apoptosis-defective Ccn1 allele are substantially resistant to TNF alpha-induced apoptosis in vivo. These results indicate that CCN1 may act as a physiologic regulator of TNF alpha cytotoxicity, providing the contextual cues from the extracellular matrix for TNF alpha-mediated cell death.