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Molecular and Cellular Biology, September 1999, p. 6229-6239, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Elevated Cyclin E Levels, Inactive Retinoblastoma Protein, and Suppression of the p27KIP1 Inhibitor Characterize Early Development of Promyeloid Cells into Macrophages

Qiang Liu,1,2 Roger W. VanHoy,1 J. H. Zhou,1 Robert Dantzer,3 Gregory G. Freund,4 and Keith W. Kelley1,*

1Department of Animal Sciences, Laboratory of Immunophysiology, and 3Department of Pathology, College of Medicine, University of Illinois, Urbana, Illinois 61801;4 INRA-INSERM U394, Institute François Magendie, 33077 Bordeaux Cedex, France; and 2Department of Hematological Oncology, Cancer Center, Sun-Yat Sen University of Medical Science, 510060 Guangzhou, People's Republic of China

Received 23 July 1998/Returned for modification 27 April 1999/Accepted 28 May 1999

Cyclin-dependent kinase inhibitors such as p27KIP1 have recently been shown to lead to cellular differentiation by causing cell cycle arrest, but it is unknown whether similar events occur in differentiating promyeloid cells. Hematopoietic progenitor cells undergo lineage-restricted differentiation, which is accompanied by expression of distinct maturation markers. Here we show that the classical growth factor insulin-like growth factor I (IGF-I) potently promotes vitamin D3-induced macrophage differentiation of promyeloid cells, as assessed by measurement of a coordinate increase in expression of the integrin alpha  subunit CD11b, the CD14 lipopolysaccharide receptor, and the macrophage-specific esterase, alpha -naphthyl acetate esterase, as early as 24 h following initiation of terminal differentiation. Addition of IGF-I to cells undergoing vitamin D3-induced differentiation also leads to an early increase in expression of cyclin E, phosphorylation of the retinoblastoma tumor suppressor protein, and a doubling of the cell number. Early expression of CD11b (24 h) is simultaneously accompanied by inhibition in the expression of p27KIP1. Cell cycle analysis with propidium iodide revealed that CD11b expression at 24 h following initiation of differentiation occurs at all phases of the cell cycle instead of only those cells arrested in G0/G1. Similarly, development of a novel double-labeling intra- and extracellular flow-cytometric technique demonstrated that single cells expressing the mature leukocyte differentiation antigen CD11b can also incorporate the thymidine analog bromodeoxyuridine. Likewise, expression of the intracellular DNA polymerase delta  cofactor/proliferating-cell nuclear antigen at 24 h is also simultaneously expressed with the surface marker CD11b, indicating that these cells continue to proliferate early in their differentiation program. Finally, at 24 h following induction of differentiation, IGF-I promoted a fourfold increase in the uptake of [3H]thymidine by purified populations of CD11b-expressing cells. Taken together, these data demonstrate that the initial steps associated with terminal macrophage differentiation occur concomitantly with progression through the cell cycle and that these very early differentiation events do not require the accumulation of p27KIP1.

* Corresponding author. Mailing address: Laboratory of Immunophysiology, University of Illinois, 207 Edward R. Madigan Laboratory, 1201 West Gregory Dr., Urbana, IL 61801. Phone: (217) 333-5141. Fax: (217) 244-5617. E-mail: kwkelley{at}uiuc.edu.

Molecular and Cellular Biology, September 1999, p. 6229-6239, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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