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 (D3)] 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 D3 reduces the dose of D3 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 D3 has been identified as the thyroid hormone 3,5,3'-L-triiodothyronine (T3). "Priming" of HL60-ITS cells with a low dose of all-trans RA reduces the amount of D3 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 T3 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 T3 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 D3, may have important therapeutic significance. Serum levels of T3 would be anticipated to influence the outcome.
Wallington
L A
LA
Department of Immunology, The Medical School, University of Birmingham, Edgbaston, U.K.
Durham
J
J
Bunce
C M
CM
Drayson
M T
MT
Brown
G
G
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D003470:Culture Media; D016895:Culture Media, Serum-Free; D004347:Drug Interactions; D004357:Drug Synergism; D018922:HL-60 Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D008775:Methylprednisolone / Q000494:pharmacology*; D008954:Models, Biological; D014212:Tretinoin / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003470:Culture Media; D016895:Culture Media, Serum-Free; D014284:Triiodothyronine; D014212:Tretinoin; D002117:Calcitriol; D008775:Methylprednisolone; D007213:Indomethacin