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Role of Tumor Necrosis Factor in Macrophage Activation and Tumoricidal Activity¹

Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14263

Tumor necrosis factor (TNF)-sensitive (LM) and -insensitive (P815) target cell lines were used to examine the role of TNF in both the activation and lytic phases of macrophage-mediated lysis. LM cells were lysed spontaneously by thioglycolate-elicited macrophages in an 18-h assay (media or activating agents added with targets) or 36-h assay (macrophages cultured with media or activating agents for 18 h, washed, and targets added for a subsequent 18 h). In contrast, P815 cells were lysed only in the 36-h assay by macrophages exposed to appropriate activation signals. Using antibody to murine TNF, it was shown that lysis of LM cells but not P815 cells was TNF mediated. The addition of lipopolysaccharide (LPS) to the 18-h assay resulted in augmented LM killing. This was probably due to the fact that LPS stimulates macrophages to produce TNF. Conversely, when macrophages were pretreated with LPS for 18 h, washed, and assessed for lytic activity during the subsequent 18 h, lysis of LM cells was reduced relative to the endogenous level.

Although macrophage lysis of P815 was not mediated by TNF, the addition of TNF to macrophage activation cultures facilitated LPS triggering of cytolytic activity against P815. Similarly, the addition of TNF to the activation cultures partially prevented the LPS-induced reduction in macrophage-mediated LM cell lysis. Taken together, these data suggest that TNF may act as an autocrine signal during macrophage activation, in addition to being directly lytic to a select number of sensitive target cell lines.

¹ Supported in part by Grants CA-15142, CA-24538, and CA-09072 awarded by the National Cancer Institute, Department of Health and Human Services, and by a grant from Asahi Chemical Industry Co. Inc.

² This work was done in partial fulfillment of the Ph.D. degree requirements in the Program of Pharmacology, Roswell Park Graduate Division, SUNY at Buffalo. Present address: Laboratory of Molecular Immunoregulation, NCI-FCRF, 560/21-89A, Frederick, MD 21701-1013.

³ To whom requests for reprints should be addressed.

Received 2/23/88. Revised 6/27/88. Accepted 7/ 6/88.

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