Lithium chloride potentiates tumor necrosis factor-induced and interleukin 1-induced cytokine and cytokine receptor expression.
The antimalignant cell activity of tumor necrosis factor (TNF) in many cell types can be enhanced by lithium chloride (LiCl). This study shows the in vitro effect of LiCl on the TNF-induced or interleukin 1 (IL-1)-induced expression of IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-2, and the IL-2 receptor-alpha (IL-2R alpha). The levels of IL-6 and GM-CSF in the medium of TNF-treated L929 fibrosarcoma cells were increased by cotreatment with LiCl. In contrast, enhancement of IL-6 production by dibutyryl cyclic AMP or cycloheximide was not affected by LiCl. The production of IL-6 and GM-CSF was not correlated with sensitivity to TNF-mediated cell killing. IL-1 by itself had no measurable effects on L929 cells. However, LiCl potentiated the IL-1-induced synthesis of IL-6, GM-CSF, IL-3, and IL-2 in PC60 murine T-cell hybridoma cells. TNF alone induced only GM-CSF production in these cells, but in the presence of LiCl, increased amounts of GM-CSF as well as small amounts of IL-2 and IL-6 could be detected. It is also shown that in these PC60 cells the expression of the IL-2R alpha was induced by TNF + LiCl treatment but not by TNF alone. IL-2R alpha expression was likewise considerably enhanced by IL-1 + LiCl treatment, as compared with treatment with IL-1 alone. The effects of LiCl on the TNF-induced and the IL-1-induced gene expression seem to be independent of the protein kinase A and C pathways. These results show that LiCl can modulate both TNF-mediated cytotoxicity and TNF-induced and IL-1-induced cytokine expression, suggesting that Li+ acts early in the TNF-signaling pathway, but at a step shared with the IL-1-signaling pathway.
Beyaert
R
R
Laboratory of Molecular Biology, State University, Gent, Belgium.
Schulze-Osthoff
K
K
Van Roy
F
F
Fiers
W
W
D000818:Animals; D002460:Cell Line; D002712:Chlorides / Q000008:administration & dosage / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis*; D004357:Drug Synergism; D007375:Interleukin-1 / Q000008:administration & dosage; D015850:Interleukin-6 / Q000096:biosynthesis; D008094:Lithium / Q000008:administration & dosage / Q000494:pharmacology*; D018021:Lithium Chloride; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000187:drug effects; D015375:Receptors, Interleukin-2 / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
D002712:Chlorides; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D008094:Lithium; D011494:Protein Kinases; D011493:Protein Kinase C; D018021:Lithium Chloride