Post-transcriptional regulation of TNF-α during in vitro differentiation of human monocytes/macrophages in primary culture

Tumor necrosis factor α (TNF‐α), a proinflammatory cytokine, is produced abundantly by monocytes and macrophages. We have compared LPS‐stimulated TNF‐α production and regulation in freshly isolated human monocytes and macrophages differentiated in vitro. A significant increase in LPS‐induced TNF‐α protein secretion was observed in macrophages over freshly isolated monocytes without comparable differences in TNF‐α mRNA induction. Polysome gradient analysis showed polysome‐mRNA distribution did not change, whereas TNF‐α mRNA stability increased in macrophages. Tristetraprolin mRNA expression was constitutive and decreased with differentiation‐linked kinetics. Blockable LPS‐inducible MAP kinase activity (p38, ERK) affected TNF‐α biosynthesis differentially at the transcriptional and post‐transcriptional level throughout the culture period. We suggest that the increase in TNF‐α secretion in macrophages relates to changes in post‐transcriptional processing, which is regulated indirectly by the expression of RNA‐binding proteins. Changes in gene expression throughout monocytic differentiation equip the cell to act as a more potent producer of this proinflammatory cytokine.