Forskolin induces U937 cell line differentiation as a result of a sustained cAMP elevation.
The present study examines the effects of forskolin on U937 cell differentiation. We recently reported that dibutyryl cAMP (dbcAMP), but not cAMP-elevating agents such as histamine, promotes U937 cell differentiation. cAMP production elicited by stimulation of histamine H2 receptors showed a rapid, homologous desensitization, which might explain the dissimilar responses to histamine and dbcAMP. Forskolin induced an increase in cAMP levels in a concentration-dependent manner (EC50=30 microM) for an extended period of at least 24 h. Forskolin but not histamine (up to 100 microM), also inhibited cell growth in a dose-dependent fashion (EC50=22 microM). After 3 days of incubation, 75 microM forskolin induced U937 cell differentiation as judged by an increased rate of reduction of nitrobluetetrazolium (mean+/-S.E.M.: 21.3+/-6.6% in treated cells vs. 3.2+/-1.9% in the control group, P < 0.001) and an augmented chemotactic response to complement 5a (C5a) (33.2+/-5.9% in forskolin-treated vs. 0.34+/-0.12% in control cells, P < 0.01). Furthermore, c-Myc levels decreased following forskolin treatment, while the histamine H2 receptor agonist dimaprit had no effect. We conclude that forskolin induces U937 cell differentiation through a sustained rise in cAMP levels.
Hematology Division, José de San Martín Clinical Hospital, School of Medicine, University of Buenos Aires, Argentina.
A
A
Brodsky
C
C
Davio
C
C
Shayo
B
B
Lemos Legnazzi
M
M
Barbosa
M
M
Lardo
A
A
Morelli
A
A
Baldi
J C
JC
Sanchez Avalos
E
E
Rivera
D000951:Antigens, Neoplasm / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016259:Genes, myc / Q000187:drug effects / Q000502:physiology; D006632:Histamine / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D005576:Colforsin; D006632:Histamine; D000242:Cyclic AMP