Reversal of TNF-alpha resistance by hyperthermia - Role of mitochondria

The aim of this study is to examine the effect of hyperthermia on tumour ne crosis factor-alpha (TNF-alpha) resistance in L929-11E cells. L929-11E is a TNF-alpha resistant variant derived from L929 cells, a commonly used model for TNF-alpha study. Based on the results from flow cytometry and Western blotting, hyperthermia (43 degreesC, 3h) was found to induce apoptosis, mit ochondrial potential (Delta Psim) depolarization and release of cytochrome c in L929-11E cells. Similar responses were found in L929 cells when treate d with TNF-alpha. Heating at 43 degreesC for 1h did not significantly damag e the mitochondria of L929-11E cells but partially reversed their resistanc e to TNF-alpha. When L929-11E cells were sequentially treated with heating (43 degreesC, 1h) and TNF-alpha, a more severe damage in mitochondria was o bserved. Taken together, our results indicate (1) hyperthermia induced apop tosis in L929-11E cells via mitochondrial damages in a way very similar to the action of TNF-alpha in L929 cells, (2) hyperthermia could be used to ov ercome TNF-alpha resistance by altering mitochondrial activities and (3) L9 29-11E and its parental cells provide a useful model in elucidating the sig nalling linkage between TNF-alpha receptor and mitochondria. (C) 2000 Elsev ier Science Inc. All rights reserved.