Hyperthermic modulation of tumor necrosis factor-dependent monocyte/macrophage tumor cytotoxicity in vitro

Tumor necrosis factor (TNF) production by human peripheral blood monocytes and murine bacillus Calmette-Guerin-activated peritoneal macrophages was strongly influenced by acute hyperthermia. If hyperthermia was administered simultaneously with or preceding lipopolysaccharide triggering, production was severely ablated by 42 degrees and 43 degrees C treatments; however, if triggering preceded heating by at least 90 min, production was either unaffected or markedly enhanced. A somewhat similar pattern was reflected with chronic heating. TNF production by murine macrophages was inhibited with 39 degrees C heating and completely blocked by 40.5 degrees C treatment, if triggering coincided with the initiation of hyperthermia. However, augmentation of production occurred with either of these temperatures if triggering preceded hyperthermia by as little as 90 min. Human monocytes demonstrated greater resistance to the deleterious effects of coincident triggering and heating with respect to TNF secretion than the rodent effectors, but the response was otherwise very similar. The TNF-sensitive phenotype of the L929 cell could be augmented by chronic or acute hyperthermia, markedly so with a 43 degrees C treatment. The TNF-resistant phenotype of the EMT-6 cell could be reversed by chronic heating at 40.5 degrees C, or by acute heating at 43 degrees C, but only if the latter followed TNF treatment. These results reflect important regulatory controls of TNF production and responses in tumor cells which are susceptible to hyperthermia manipulation.