Heat-shock proteins protect cells from monocyte cytotoxicity: possible mechanism of self-protection.
We have previously shown that major heat-shock protein (hsp 70) protects WEHI-S tumor cells from cytotoxicity mediated by tumor necrosis factor alpha (TNF-alpha) and TNF-beta. In the present study, the effect of altered expression of hsp70 and low molecular weight heat-shock protein, hsp27, on tumor cell sensitivity to monocytes and lymphokine-activated killer (LAK) cells was studied. Constitutive and stable expression of transfected human hsp70 rendered cells almost completely resistant to monocytes. Conversely, inhibition of endogenous hsp70 by expression of antisense hsp70 RNA enhanced the sensitivity of cells to monocyte-mediated killing. Surprisingly, overexpression of human hsp27, which does not protect WEHI-S cells from TNF killing, conferred partial resistance to monocytes. Only approximately 60% of monocyte-mediated killing of WEHI-S cells could be blocked by neutralizing TNF-alpha antibody or immunoglobulin G-TNF receptor chimeric protein, suggesting the presence of both TNF-dependent and TNF-independent lytic mechanisms. As free radicals have been suggested to be mediators of monocyte cytotoxicity, we tested the sensitivity of transfected cells to oxidative stress. Overexpression of either hsp70 or hsp27 rendered cells partially resistant to hydrogen peroxide. No significant changes in the susceptibility of cell lines overexpressing hsp70 or hsp27 to cytotoxicity mediated by LAK cells were observed. Interestingly, monocytes but not LAK cells contained detectable levels of hsp27 and hsp70 in nonstressed conditions. Taken together, these data indicate that hsp70 protects tumor cells from TNF-mediated monocyte cytotoxicity and that both hsp27 and hsp70 confer resistance to TNF-independent, probably free radical-mediated lysis by monocytes. Moreover, hsp27 and hsp70 may provide monocytes with a protective mechanism against their own toxicity.
Jäättelä
M
M
Department of Tumor Cell Biology, Fibiger Institute, Danish Cancer Society, Copenhagen.
Wissing
D
D
D000818:Animals; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000032:analysis / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000737:chemistry / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000737:chemistry / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D006360:Heat-Shock Proteins; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide