Synergy between transforming growth factor-β and tumor necrosis factor-α in the induction of monocytic differentiation of human leukemic cell lines

Abstract

We examined the effect of transforming growth factor-β (TGF-β) alone and in combinations with other factors on the growth and differentiation of the human promyelocytic cell line HL60 and the human monoblastic cell line U937. Treatment with TGF-β alone did not significantly affect growth or differentiation of HL60 cells, while it significantly inhibited proliferation and induced monocytic differentiation of a small percentage of U937 cells. Combinations of TGF-β and tumor necrosis factor-α (TNF-α) acted in synergy to inhibit cell proliferation and to induce monocytic differentiation of both HL60 and U937 cells. In contrast, no synergy was observed when HL60 cells were treated with TGF-β in various combinations with interferon-α (IFN-α), interferon-γ (IFN-γ), and retinoic acid. Examination of TNF-α receptor expression on HL60 and U937 cells showed that these cell lines expressed comparable levels of high-affinity TNF-α binding sites. Treatment of HL60 and U937 cells with TGF-β did not induce significant changes in TNF-α receptor expression in either cell line. In contrast, HL60 cells expressed much lower levels of TGF-β receptors than did U937 cells. Treatment of both HL60 and U937 cells with TNF-β induced a dose-dependent increase in expression of TGF-β receptors, suggesting that the synergy between TNF-α and TGF-β may result, at least in part, from upregulation of TGF-β receptor expression by TNF-α. This is a US government work. There are no restrictions on its use.