A role for the NF-κB pathway in cell protection from complement-dependent cytotoxicity.
Nucleated cells are equipped with several mechanisms that support their resistance to complement-dependent cytotoxicity (CDC). The role of the NF-κB pathway in cell protection from CDC was examined. Elevated sensitivity to CDC was demonstrated in cells lacking the p65 subunit of NF-κB or the IκB kinases IKKα or IKKβ, and in cells treated with p65 small interfering RNA. Pretreatment with the IKK inhibitor PS-1145 also enhanced CDC of wild-type cells (WT) but not of p65(-/-) cells. Furthermore, reconstitution of p65 into p65(-/-) cells and overexpression of p65 in WT cells lowered their sensitivity to CDC. The postulated effect of p65 on the JNK-mediated death-signaling pathway activated by complement was examined. p65 small interfering RNA enhanced CDC in WT cells but not in cells lacking JNK. JNK phosphorylation induced by complement was more pronounced in p65(-/-) cells than in WT cells. The results indicate that the NF-κB pathway mediates cell resistance to CDC, possibly by suppressing JNK-dependent programmed necrotic cell death.
Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Dana
D
Gancz
Michal
M
Lusthaus
Zvi
Z
Fishelson
D000818:Animals; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D003167:Complement Activation / Q000235:genetics / Q000276:immunology*; D015938:Complement Membrane Attack Complex / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology*; D053595:Embryonic Stem Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D021122:Protein Subunits / Q000172:deficiency; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051996:Transcription Factor RelA / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*
D015938:Complement Membrane Attack Complex; D021122:Protein Subunits; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase; D048670:MAP Kinase Kinase 4