Lymphotoxin: Stimulation and regulation of colony-stimulating factors in fibroblasts

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Abstract

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 the 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 α (TNFα) was about five times more potent than lymphotoxin at low concentrations, and was nearly 1.5 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.

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Akashi, M., Saito, M., & Koeffler, H. P. (1989). Lymphotoxin: Stimulation and regulation of colony-stimulating factors in fibroblasts. Blood, 74(7), 2383–2390. https://doi.org/10.1182/blood.v74.7.2383.bloodjournal7472383

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