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 diffe rentiation. We recently reported that dibutyryl cAMP (dbcAMP), but not cAMP-elevating agents such as histamine, promotes U937 cell different iation. cAMP production elicited by stimulation of histamine H-2 recep tors showed a rapid, homologous desensitization, which might explain t he dissimilar responses to histamine and dbcAMP. Forskolin induced an increase in cAMP levels ina concentration-dependent manner (EC50 = 30 mu M) for an extended period of at least 24 h. Forskolin but not hista mine (up to 100 mu M), also inhibited cell growth in a dose-dependent fashion (EC50 = 22 mu M). After 3 days of incubation, 75 mu M forskoli n induced U937 cell differentiation as judged by an increased rate of reduction of nitrobluetetrazolium (mean +/- S.E,M.: 21.3 +/- 6.6% in t reated 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% i n forskolin-treated vs. 0.34 +/- 0.12% in control cells, P < 0.01). Fu rthermore, c-Myc levels decreased following forskolin treatment, while the histamine H-2 receptor agonist dimaprit had no effect. We conclud e that forskolin induces U937 cell differentiation through a sustained rise in cAMP levels. (C) 1998 Elsevier Science B.V. All rights reserv ed.