Hyperthermic modulation of respiratory inhibition factor- and iron releasing factor-dependent macrophage murine tumor cytotoxicity.

Hyperthermia modulated the cytotoxic activities of murine macrophages cocultured with EMT-6 tumor cells, altered the production of the monokines RIF (respiratory inhibition factor) and FeRF (iron-releasing factor) by these effector cells, and perturbed the activities of these monokines against EMT-6 cells. Cytotoxic activities of heated murine macrophages activated by Bacillus Calmette-Guérin were inhibited by heat doses of 40.5 degrees C for greater than or equal to 1 h if heating preceded triggering by the endotoxin lipopolysaccharide; however, cytotoxic activities were better retained if triggering preceded heating by 2 h. Treatment-sequence dependencies were also found in the secretion of some monokines that participate in these macrophage cytotoxic effects. Secretion of both RIF and FeRF by macrophages was slightly augmented or at least better retained if triggering of macrophages occurred several hours before heating for 1 h at 40.5-43 degrees C or for 24 h at 39-40.5 degrees C. If heating was nearly simultaneous with triggering or preceded it by several hours, there was a dose-dependent decrease in monokine secretion. The sensitivity of tumor cell targets to these monokines was also modified by the treatment sequence. When EMT-6 cells were treated with RIF- or FeRF-containing macrophage conditioned supernatants 1 h before heating at 40.5-43 degrees C, the RIF-treated cells became sensitized and the FeRF-treated cells retained better cytotoxic response than if cells had been treated 1 h after heating. Chronic heating for 24 h at 39-40.5 degrees C showed less dependence of tumor cell response on treatment sequence. Similar observations have recently been made in our laboratory for the interaction of tumor necrosis factor cytotoxic pathways with hyperthermia (Klostergaard et al., J. Biol. Response Modif., in press, 1989; Tomasovic et al., Int. J. Hyperthermia, in press, 1989). Those results and the present observations with the monokines RIF and FeRF support our hypothesis that the cytotoxic actions of macrophages and the cytotoxicity of endogenously added monokines can be augmented by appropriately constructed sequences combining hyperthermia with either macrophage priming/triggering or monokine treatment of tumor cells.