MACROPHAGE-DERIVED TUMOR-NECROSIS-FACTOR AND TUMOR-DERIVED OF LEUKEMIA INHIBITORY FACTOR AND INTERLEUKIN-6 - POSSIBLE CELLULAR MECHANISMS OF CANCER CACHEXIA

Background: The cellular basis for augmented cytokine production in th e tumor-bearing host is not known. Recently leukemia inhibitory factor (LIF) and interleukin (IL)-6, produced by a variety of tumors, have b een implicated as mediators of cachexia. Methods: Five murine tumor ce ll lines were tested for the production of these cytokines. 4JK tumor was further tested to determine if IL-1, tumor necrosis factor (TNF), or cocultivation with RAW 264 cells augmented IL-6 or LIF production. Results: 4JK from in vivo tumors produced significantly more IL-6 than did 4JK from culture, indicating that tumor production of IL-6 and LI F is potentially augmented by infiltrating macrophages. When 4JK was c ocultured with RAW 264 cells, TNF, or IL-1 in vitro, a three- to 15-fo ld increase in tumor production of LIF and IL-6 was noted (p(2) less t han or equal to 0.03). Conversely, in coculture experiments performed with a neutralizing TNF antibody, a 50% reduction in tumor production of LIF and IL-6 was noted (p(2) < 0.04). Resting RAW cells produced on ly minimal quantities of TNF; however, when RAW cells were exposed to tumor-conditioned supernatant from 4JK, their TNF production was marke dly increased. Conclusions: In the tumor microenvironment, host macrop hages may be activated and produce inflammatory cytokines such as TNF. Local TNF then appears to act on tumor cells to stimulate production of IL-6 and LIF. Enhanced tumor production of cytokine mediators may c ontribute to deleterious effects of neoplastic growth on the host.