Necrosis is associated with IL-6 production but apoptosis is not.
Due to loss of cell membrane integrity, necrotic cells passively release several cytosolic factors that can activate antigen presenting cells and other immune cells. In contrast, cells dying by apoptosis do not induce an inflammatory response. Here we show that necrotic cell death induced by several stimuli, such as TNF, anti-Fas or dsRNA, coincides with NF-kappaB-and p38MAPK-mediated upregulation and secretion of the pro-inflammatory cytokine IL-6. This event is greatly reduced or absent in conditions of apoptotic cell death induced by the same stimuli. This demonstrates that besides the capacity of necrotic cells to induce an inflammatory response due to leakage of cellular contents, necrotic dying cells themselves are involved in the expression and secretion of inflammatory cytokines. Moreover, inhibition of NF-kappaB and p38MAPK activation does not affect necrotic cell death in all conditions tested. This suggests that the activation of inflammatory pathways is distinct from the activation of necrotic cell death sensu strictu.
Vanden Berghe
Tom
T
Molecular Signalling and Cell Death Unit, Department for Molecular Biomedical Research, VIB and Ghent University, Technologiepark 927, B-9052, Ghent (Zwijnaarde), Belgium.
Kalai
Michael
M
Denecker
Geertrui
G
Meeus
Ann
A
Saelens
Xavier
X
Vandenabeele
Peter
P
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D019892:eIF-2 Kinase / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D061945:Caspase Inhibitors; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C411023:anti-Fas monoclonal antibody; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases