Cytotoxicity of TNFα is regulated by integrin-mediated matrix signaling

Abstract

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 TNFα is cytotoxic to certain tumor cell lines, it induces apoptosis in normal cells only when NFκB signaling is blocked. Here we show that the matricellular protein CCN1/CYR61 can unmask the cytotoxic potential of TNFα without perturbation of NFκB signaling or de novo protein synthesis, leading to rapid apoptosis in the otherwise resistant primary human fibroblasts. CCN1 acts through binding to integrins αvβ5, α6β1, 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 TNFα‐induced apoptosis in vivo. These results indicate that CCN1 may act as a physiologic regulator of TNFα cytotoxicity, providing the contextual cues from the extracellular matrix for TNFα‐mediated cell death.

Rac1-mediated Mitochondrial H2O2 Generation Regulates MMP-9 Gene Expression in Macrophages via Inhibition of SP-1 and AP-1

“…Another important source of H 2 O 2 is the mitochondria. Rac1 modulation of mitochondrial ROS generation has only been described in fibroblasts via engagement of integrins (44,45). Our study is the first to demonstrate that Rac1 induces H 2 O 2 generation from the mitochondria in macrophages.…”

Research on WISP1 in Lung Disease

“…Integrins appear to regulate inflammatory responses such as TNF release [71]. Indeed, RGD-(Arg-Gly-Asp-Ser peptides) sensitive integrin signaling in VILI [72] and αvβ3 and αvβ5 in particular have been identified to play critical roles in regulating pulmonary permeability in ALI and VILI [73].…”

“…cysteinerich protein 61 (CCN1) via αvβ3 [68], CCN3 via αvβ5 [69], and WISP1 (CCN4) via αvβ3 [70] to induce intracellular signaling events [2,8]. Integrins appear to regulate inflammatory responses such as TNF release [71]. Indeed, RGD-(Arg-Gly-Asp-Ser peptides) sensitive integrin signaling in VILI [72] and αvβ3 and αvβ5 in particular have been identified to play critical roles in regulating pulmonary permeability in ALI and VILI [73].…”

Regulation of CCN2 mRNA expression and promoter activity in activated hepatic stellate cells

“…CCN2 appears to be a key contributor to the fibrogenic phenotype of HSC in that CCN2 promotes proliferation, adhesion, and collagen production of this cell type through integrins and HSPGs . Through its role as a pro-adhesive matricellular molecule, CCN2 can also amplify adhesive signaling emanating from other pro-fibrotic ligands such as fibronectin and TGFβ, and pro-inflammatory ligands such as TNFα Chen et al 2004Chen et al , 2007. Moreover, CCN2-deficient mouse embryonic fibroblasts show impairment of a myriad of fibrogenic activity, inclusing cell adhesion, matrix contraction, and gene expression Kennedy et al 2007;Pala et al 2008).…”