Endogenous D-factor activity partially mediates the toxic but not the therapeutic effects of tumor necrosis factor.
We have earlier shown that passive immunization against differentiation-inducing factor/leukemia-inhibitory factor (D factor) activity improves the survival of endotoxemic mice, suggesting that D factor may contribute to the systemic toxicity associated with tumor necrosis factor (TNF). In the current experiments, TNF induced D-factor gene expression in various tissues of non-tumor-bearing female C57BI/6 mice. Passive immunization against D-factor significantly improved survival after a lethal TNF challenge in both non-tumor-bearing (p2 < 0.02) and tumor-bearing mice (p2 < 0.01). In mice bearing 10-day s.c. MCA 105 sarcomas, D-factor antibody alone had no effect on tumor growth as compared with control IgG. Tumor regression and regrowth in mice treated i.v. with TNF was not affected by pre-treatment with D-factor antibody, as compared with pre-treatment with IgG. However, TNF-treatment-related mortality was abrogated by pre-treatment with D-factor antibody (0% vs. 36% for IgG-pre-treated controls). These results indicate that endogenous D-factor activity contributes to the toxicity but not to the anti-tumor effects of TNF therapy. With renewed interest in the use of TNF for the treatment of patients with cancer, improved understanding of the role of D factor in mediating the effects of TNF may have important clinical benefits.
Block
M I
MI
Surgical Metabolism Section, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Fraker
D L
DL
Strassmann
G
G
Billingsley
K G
KG
Arnold
W S
WS
Perlis
C
C
Alexander
H R
HR
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006131:Growth Inhibitors / Q000502:physiology* / Q000633:toxicity; D007116:Immunization, Passive; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000502:physiology* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D017931:DNA Primers; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha