Influences of interleukins 2 and 4 on tumor necrosis factor production by murine mononuclear phagocytes.

Administration of recombinant human interleukin 2 (IL-2) to mice gave rise to peritoneal macrophages and blood monocytes that were primed to produce large amounts of tumor necrosis factor (TNF). Macrophages from IL-2-treated athymic mice responded less well than those from euthymic mice. In addition to its in vivo priming effect, IL-2 was able to directly stimulate TNF production in vitro by purified monocytes. Macrophages responded to IL-2 generally less well than monocytes both in vitro and in vivo. In contrast to IL-2, recombinant murine interleukin 4 (IL-4) down-regulated TNF synthesis by macrophages. In vitro pretreatment of macrophages with IL-4 largely abolished their ability to synthesize TNF in response to IL-2 or lipopolysaccharide. Also, administration of IL-4 to mice blocked the ability of IL-2 and lipopolysaccharide to prime macrophages in vivo for TNF production. Overall, these results demonstrate that IL-2 and IL-4 can act antagonistically to regulate TNF production by macrophages. In spite of its down-regulatory action on TNF production, IL-4 was unable to protect mice against the lethal toxic effects of lipopolysaccharide or IL-2.

Genetic modification of a murine fibrosarcoma to produce interleukin 7 stimulates host cell infiltration and tumor immunity.

Retroviral-mediated gene transfer was used to introduce and express the gene for murine interleukin 7 (IL-7) in a fibrosarcoma tumor (FSA). The tumorigenicity of these genetically modified FSA cells was greatly decreased in immunologically intact syngeneic mice but was unaltered in T-cell-deprived mice. IL-7-infected tumors that did grow in intact animals from large size inocula did so slowly and had a high incidence of spontaneous regression. Furthermore, mice that had rejected tumors became specifically immune to challenge with uninfected parental tumor cells. IL-7-infected FSA growing in intact mice were heavily infiltrated with host T-cells that were presumably responsible for slow growth and tumor regression, and tumor cells were in the minority. Fluorescence-activated cell sorter analysis showed that there was a 530% increase in T-cells in IL-7-infected FSA compared with control tumors. CD8+ T-cells were particularly elevated, but CD4+ lymphocytes were also increased in number, as were eosinophils and basophils. The CD4+:CD8+ ratio in IL-7-infected FSA was 1:1.7 in comparison to 1:0.6 in control tumors. Lymphocytes isolated from IL-7-producing tumors had greatly enhanced cytotoxicity towards uninfected, parental FSA cells. Killing of non-cross-reacting fibrosarcoma line was also increased but to a much lesser extent. Injection of recombinant human IL-7 directly into established FSA tumors slowed their growth and, in a significant number of instances, caused complete regression. Mice that had rejected tumor became specifically immune. The dose that was needed for this effect was, however, somewhat large: 20 micrograms twice daily for 10 days. This result contrasts with the efficacy of IL-7 gene infection in stimulating responses to the same tumor. These considerations make IL-7 a good candidate for tumor-directed cytokine gene therapy.