The involvement of an LPS inducible I kappa B kinase in endotoxin tolerance.
When human ovarian carcinoma cells are challenged with endotoxin, an I kappa B kinase is transiently induced within 3 to 5 min. This enzyme activity causes the hyperphosphorylation and subsequent degradation of I kappa B which allows NF-kappa B to translocate to the nucleus where it activates transcription. When endotoxin treated cells are rechallenged with a second dose of LPS, I kappa B kinase is not detected and I kappa B remains in the cytoplasm where it sequesters NF-kappa B. We report here the absence of endotoxin inducible I kappa B kinase activity in endotoxin tolerant cells suggesting that I kappa B kinase may play an important role in endotoxin tolerance. When cells tolerant to endotoxin are treated with TNF, I kappa B kinase activity is induced. Thus cells that are endotoxin tolerant are not cross tolerant to TNF. Dexamethasone, a known inhibitor of NF-kappa B activation does not inhibit endotoxin dependent induction of I kappa B kinase suggesting that the mechanism of action of dexamethasone is different from the tolerance mechanism reported here.
Kohler
N G
NG
CV Therapeutics, Inc., Palo Alto, California 94304, USA.
Joly
A
A
D001483:Base Sequence; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004361:Drug Tolerance; D004731:Endotoxins / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase; D008070:Lipopolysaccharides / Q000633:toxicity*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004731:Endotoxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human