The Involvement of an LPS Inducible IκB Kinase in Endotoxin Tolerance

When human ovarian carcinoma cells are challenged with endotoxin, an IκB kinase is transiently induced within 3 to 5 min. This enzyme activity causes the hyperphosphorylation and subsequent degradation of IκB which allows NF-κB to translocate to the nucleus where it activates transcription. When endotoxin treated cells are rechallenged with a second dose of LPS, IκB kinase is not detected and IκB remains in the cytoplasm where it sequesters NF-κB. We report here the absence of endotoxin inducible IκB kinase activity in endotoxin tolerant cells suggesting that IκB kinase may play an important role in endotoxin tolerance. When cells tolerant to endotoxin are treated with TNF, IκB kinase activity is induced. Thus cells that are endotoxin tolerant are not cross tolerant to TNF. Dexamethasone, a known inhibitor of NF-κB activation does not inhibit endotoxin dependent induction of IκB kinase suggesting that the mechanism of action of dexamethasone is different from the tolerance mechanism reported here.