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Differentiation of U-937 Histiocytic Lymphoma Cells towards Mature Neutrophilic Granulocytes by Dibutyryl Cyclic Adenosine-3',5'-monophosphate¹

Departments of Pharmacology and Toxicology, Rutgers University, Environmental and Community Medicine, UMDNJ-Robert Wood Johnson Medical School, and Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854

Treatment of U-937 cells with the cyclic nucleotide analog, dibutyryl cyclic adenosine-3',5'-monophosphate (dBcAMP) induced these cells to differentiate towards granulocytes. dBcAMP produced a dose- and time-dependent inhibition of U-937 cell growth reaching a maximum after 48-h treatment with 500 µM. At this concentration, dBcAMP had no effect on cell viability. Treatment with dBcAMP caused a rapid (within 24 h) decrease in the number of cells in the S phase of the cell cycle, with a concomitant increase in cells in the G₀/G₁ phase. dBcAMP also induced the appearance of f-met-leu-phe receptors on U-937 cells as well as the ability to produce hydrogen peroxide and superoxide anion. These data suggest that dBcAMP-treated U-937 cells were functionally mature. Using specific monoclonal antibodies and flow cytometry, we found that differentiated U-937 cells expressed the monocytic/granulocytic surface markers MY8 and MAC-1, but not the monocyte specific markers MO2 or MY4. In addition, dBcAMP-treated U-937 cells did not stain for nonspecific esterase, displayed less HLA-DR antibody binding than undifferentiated cells and appeared smaller and more granular. These are all characteristics of mature granulocytes. Taken together our studies indicate that differentiation of U-937 cells is not necessarily limited to the monocytic pathway of development.

¹ This work was supported by NIH grants AI20183 and GM34310 awarded to D. L. L.

² To whom requests for reprints should be addressed.

Received 3/ 2/89. Revised 8/ 1/89. Accepted 10/ 2/89.

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