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Hyperthermic modulation of respiratory inhibition factor- and iron releasing factor-dependent macrophage murine tumor
J Klostergaard1, M Barta, S P Tomasovic
1Department of Tumor Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Abstract:
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.
Insights
Hyperthermia timing affects macrophage cancer cell killing. Optimal sequences of heat and immune cell activation enhance cytotoxic activity and monokine effectiveness against tumors.
Area of Science:
- Immunology
- Oncology
- Biophysics
Background:
- Murine macrophages and monokines play a role in tumor cell cytotoxicity.
- Hyperthermia is known to modulate immune cell functions and tumor cell sensitivity.
- The sequence of hyperthermia application relative to immune cell activation and tumor cell treatment is critical.
Purpose of the Study:
- To investigate the impact of hyperthermia timing on macrophage-mediated cytotoxicity against EMT-6 tumor cells.
- To determine how hyperthermia affects the production and activity of monokines respiratory inhibition factor (RIF) and iron-releasing factor (FeRF).
- To explore the influence of treatment sequence on tumor cell sensitivity to monokines under hyperthermia.
Main Methods:
- Murine macrophages were cocultured with EMT-6 tumor cells under various hyperthermia conditions.
- Macrophage activation was achieved using Bacillus Calmette-Guérin and lipopolysaccharide.
- Monokine production (RIF, FeRF) and cytotoxic activities were measured.
- EMT-6 cells were treated with monokine-containing supernatants before or after hyperthermia exposure.
Main Results:
- Hyperthermia inhibited macrophage cytotoxic activity when applied before lipopolysaccharide triggering, but retained activity when triggering preceded heating.
- Macrophage secretion of RIF and FeRF was augmented or retained when triggering preceded heating, but decreased with simultaneous or preceding heating.
- Tumor cell sensitivity to RIF and FeRF was sequence-dependent, with pre-heating sensitization observed for RIF and retained cytotoxicity for FeRF.
Conclusions:
- The sequence of applying hyperthermia in relation to macrophage activation and tumor cell treatment significantly impacts anti-tumor efficacy.
- Optimized sequences of hyperthermia and immune modulation can enhance macrophage cytotoxicity and monokine effectiveness.
- These findings support the hypothesis that hyperthermia can augment cytotoxic actions through carefully constructed treatment protocols.