Cytotoxicity of TNFalpha 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 TNFalpha is cytotoxic to certain tumor cell lines, it induces apoptosis in normal cells only when NFkappaB signaling is blocked. Here we show that the matricellular protein CCN1/CYR61 can unmask the cytotoxic potential of TNFalpha without perturbation of NFkappaB 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 TNFalpha-induced apoptosis in vivo. These results indicate that CCN1 may act as a physiologic regulator of TNFalpha cytotoxicity, providing the contextual cues from the extracellular matrix for TNFalpha-mediated cell death.
Chen
Chih-Chiun
CC
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL 60607, USA.
Young
Jennifer L
JL
Monzon
Ricardo I
RI
Chen
Ningyu
N
Todorović
Viktor
V
Lau
Lester F
LF
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D007231:Infant, Newborn; D016023:Integrins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D016023:Integrins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019255:NADPH Oxidases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3