Lymphotoxin: stimulation and regulation of colony-stimulating factors in
fibroblasts
M Akashi, M Saito and HP Koeffler
Department of Medicine, University of California, Los Angeles.
Colony-stimulating factors (CSFs) are pivotal for proliferation and
function of hematopoietic cells. We found that lymphotoxin, a product of
activated lymphocytes, stimulates accumulation of granulocyte- macrophage
(GM)-CSF and macrophage (M)-CSF proteins and mRNAs in fibroblasts. An
increase in GM- and M-CSF mRNA levels occurred within 2 hours after
addition of 1,000 U/mL lymphotoxin and levels plateaued over the next 24
hours. Tumor necrosis factor alpha (TNF alpha) was about five times more
potent than lymphotoxin at low concentrations, and was nearly 1.5 to to 2
times more potent at maximally stimulating concentrations of the cytokines.
Stimulation by lymphotoxin did not require either new protein synthesis or
protein kinase-C stimulation. Stability studies of GM- and M-CSF
transcripts in fibroblasts showed that M-CSF mRNA was five times more
stable (half-life [t 1/2], 100 minutes) than GM-CSF mRNA (t 1/2, 20
minutes). Stability of these mRNAs was unchanged after stimulation of the
cells with lymphotoxin. In addition, exposure of cells to
12-O-tetradecanoylphorbol 13-acetate did not alter stability of M-CSF mRNA
but markedly prolonged the stability of GM-CSF mRNA. This is consistent
with data showing that the AT-rich consensus region in the 3' untranslated
region of many transiently expressed cytokines including GM-CSF but not
M-CSF, play a major role in their mRNA stability. Our results suggest that
activated lymphocytes can affect hematopoietic cell function and growth by
stimulating production of CSFs by mesenchymal cells.
Volume 74,
Issue 7,
pp. 2383-2390,
11/15/1989
Copyright © 1989 by The American Society of Hematology
