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 the tumor-bearing host is not known. Recently leukemia inhibitory factor (LIF) and interleukin (IL)-6, produced by a variety of tumors, have been implicated as mediators of cachexia.


METHODS
Five murine tumor cell 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 LIF is potentially augmented by infiltrating macrophages. When 4JK was cocultured with RAW 264 cells, TNF, or IL-1 in vitro, a three- to 15-fold increase in tumor production of LIF and IL-6 was noted (p2 < or = 0.03). Conversely, in coculture experiments performed with a neutralizing TNF antibody, a 50% reduction in tumor production of LIF ad IL-6 was noted (p2 < 0.04). Resting RAW cells produced only minimal quantities of TNF; however, when RAW cells were exposed to tumor-conditioned supernatant from 4JK, their TNF production was markedly increased.


CONCLUSIONS
In the tumor microenvironment, host macrophages 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 contribute to deleterious effects of neoplastic growth on the host.
Billingsley
K G
KG
National Cancer Institute/National Institutes of Health, Bethesda, MD 20892, USA.
Fraker
D L
DL
Strassmann
G
G
Loeser
C
C
Fliot
H M
HM
Alexander
H R
HR
D000818:Animals; D000906:Antibodies / Q000276:immunology; D002100:Cachexia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D006131:Growth Inhibitors / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D009374:Neoplasms, Experimental / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
D000906:Antibodies; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D014409:Tumor Necrosis Factor-alpha