Triiodothyronine blocks potentiation of HL60 monocyte differentiation by anti-inflammatory agents and by steroids and induces apoptosis of all-trans retinoic acid ''primed'' cells

Sensitivity of the human promyeloid cell line HL60 to physiological differentiating agents [e.g. all-trans retinoic acid (all-trans RA) and 1 alpha,25-dihydroxyvitamin (D-3)] is increased by exposure of cells to ''anti-inflammatory agents'' (e.g. indomethacin) and to steroids [e.g. medroxyprogesterone acetate (MPA)] and post ''priming'' with a low dose (10(-8) M) of all-trans RA. Co-treatment of serum free-grown HL60 cells (HL60-ITS) with indomethacin and D-3 reduces the dose of D-3 required for monocyte differentiation from 10(-7) to 6.25 x 10(-9) M. This potentiating effect was observed to be almost absent when experiments where undertaken using serum-grown HL60 cells (HL60-FCS). The agent present in serum that interferes with indomethacin-and MPA-potentiation of the sensitivity of HL60 cells to D-3 has been identified as the thyroid hormone 3,5,3'-L-triiodothyronine (T-3). ''Priming'' of HL60-ITS cells with a low dose of all-trans RA reduces the amount of D-3 required for the induction of monocyte differentiation to the same degree as co-treatment with either indomethacin or MPA (to 5 x 10(-9) M). However, the combined effect of all-trans RA ''priming'' and Tg treatment of HL60-ITS cells was induction of apoptosis. Treatment with either agent alone did not result in increased levels of apoptotic cells. These data reveal that T-3 has an important influence on the capacity of HL60 cells to undergo differentiation and can promote apoptosis of these cells. Drug combinations, such as a differentiation potentiating agent, for example, indomethacin or MPA, and a differentiation inducer, for example, all-trans RA or D-3. may have important therapeutic significance. Serum levels of T-3 would be anticipated to influence the outcome. (C) 1997 Elsevier Science Ltd.