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.