Tumor necrosis factor alpha and interferon gamma--induced cell growth arrest is mediated via insulin-like growth factor binding protein-3.
Retinoic acid (RA), and the combination of TNFalpha and Interferon (IFN-gamma) inhibit human salivary gland tumor (HSG) cell growth with the combination of all three being even more inhibitory (P<0. 05). Previous studies have demonstrated that these inhibitory effects of RA, and the combination of TNFalpha and IFN-gamma are associated with increased accumulation of IGFBP-3 in the culture medium of HSG cells. Therefore, we set out to determine if the increase in IGFBP-3 was due to increased production of IGFBP-3 by the cells and whether IGFBP-3 played a causative role in the inhibition of cellular proliferation. TNFalpha and IFN-gamma induced a rise in IGFBP-3 mRNA levels between 4 and 8 h, which returned to control levels after 24 h. IGFBP-3 was shown to inhibit HSG cell growth at concentrations of >/=75 U (P<0.05). When antibodies to IGFBP-3 were used with TNFalpha and IFN-gamma, the inhibitory effect of the cytokines on cell growth was diminished. Retinoic acid with TNFalpha and IFN-gamma had a marked inhibitory effect (P<0.05) which was similarly reversed by increasing concentrations of IGFBP-3 antibody. The present data support the hypothesis that the combination of TNFalpha and IFN-gamma with retinoic acid exert their anti-proliferative effect on HSG cells by reducing the mitogenic effect of IGF-I due to a shift in IGF-I from the free to the IGFBP-3-bound form.
Katz
J
J
Heller Institute of Medical Research, Sheba Medical Center, Dept. of Clinical Biochemistry, Sackler School of Medicine Tel-Aviv University, Tel-Aviv, Israel.
Nasatzky
E
E
Werner
H
H
Le Roith
D
D
Shemer
J
J
D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D005786:Gene Expression Regulation; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D016207:Cytokines; D018972:Insulin-Like Growth Factor Binding Protein 3; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma