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Role of Tumor Necrosis Factor and Interleukin 1 in -Interferon-promoted Activation of Mouse Tumoricidal Macrophages¹

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

The purpose of this study was to determine if recombinant murine interleukin 1ß (rMu-IL-1ß) alone or in combination with recombinant murine -interferon (rMu-IFN-) could activate murine macrophages to be tumoricidal against tumor necrosis factor (TNF)-insensitive target cells and to evaluate the possible role of interleukin 1 (IL-1) in murine macrophage activation by recombinant murine tumor necrosis factor (rMu-TNF) plus rMu-IFN-. rMu-IL-1ß and rMu-TNF alone or in combination could neither directly lyse the TNF-insensitive P815 mastocytoma nor activate resident peritoneal macrophages to be tumoricidal for this target. A synergistic induction of tumoricidal macrophage activity against P815 occurred, however, when either of these monokines was combined with rMu-IFN-. The tumoricidal activity obtained was transitory, and the level of activity was dependent upon the monokine concentration and the length of induction period. Murine macrophages stimulated under the same conditions used to induce tumoricidal activity with rMu-TNF plus rMu-IFN- or with rMu-IL-1 plus rMu-IFN- were shown to produce low concentrations of IL-1 or TNF, respectively. Thus, a bidirectional cross-induction of the production of the two monokines occurred. The monokine production was also quite transitory, and the time of peak production of the monokines (12 h) was found to precede the time of peak tumoricidal activation (24 h). Using neutralizing antisera specific for rMu-IL-1s and rMu-TNF, the cross-induced production of TNF was shown to be required for macrophage tumoricidal activation by rMu-IL-1ß alone (TNF-sensitive targets) or in combination with rMu-IFN- (TNF-insensitive targets). There was no evidence, however, that the production of IL-1 was required for macrophage activation by rMu-TNF in combination with rMu-IFN-.

¹ This study was supported in part by the Asahi Chemical Industry Co., Ltd.; by USPHS Grants CA-24538 and CA-13038 awarded by the National Cancer Institute, Department of Health and Human Services; and by Grant IFN-18 awarded by the American Cancer Society.

² To whom requests for reprints should be addressed, at Grace Cancer Drug Center, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY 14263.

Received 10/24/88. Revised 2/14/89. Accepted 2/17/89.