The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/12/1583/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 11, December 6, 1999 1583-1594

Original Article

1{alpha},25-Dihydroxyvitamin D3–induced Myeloid Cell Differentiation Is Regulated by a Vitamin D Receptor–Phosphatidylinositol 3-Kinase Signaling Complex

Zakaria Hmamaa,c, Devki Nandana, Laura Slya, Keith L. Knutsona, Patricia Herrera-Velita, and Neil E. Reinera,b
a Department of Medicine (Division of Infectious Diseases), The University of British Columbia, Faculties of Medicine and Science, The Research Institute of the Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia, Canada V5Z 3J5
b Department of Microbiology and Immunology, The University of British Columbia, Faculties of Medicine and Science, The Research Institute of the Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia, Canada V5Z 3J5
c Laboratoire d'Immunologie, Faculté des Sciences Dhar Mahraz, Université Mohamed Ben Abdallah, Fès, Morocco BP1796

Correspondence to: Neil E. Reiner, Division of Infectious Diseases, University of British Columbia, Rm. 452D, 2733 Heather St., Vancouver, BC, Canada, V5Z 3J5. Tel:604-875-4011 Fax:604-875-4013 E-mail:ethan{at}interchange.ubc.ca.

1{alpha},25-dihydroxyvitamin D3 (D3) promotes the maturation of myeloid cells and surface expressions of CD14 and CD11b, markers of cell differentiation in response to D3. To examine how these responses are regulated, THP-1 cells were grown in serum-free medium and incubated with D3. This was associated with rapid and transient increases in phosphatidylinositol 3-kinase (PI 3-kinase) activity. Furthermore, induction of CD14 expression in response to D3 was abrogated by (a) the PI 3-kinase inhibitors LY294002 and wortmannin; (b) antisense oligonucleotides to mRNA for the p110 catalytic subunit of PI 3-kinase; and (c) a dominant negative mutant of PI 3-kinase. In THP-1 cells, induction of CD11b expression by D3 was also abrogated by LY294002 and wortmannin. Similarly, LY294002 and wortmannin inhibited D3-induced expression of both CD14 and CD11b in peripheral blood monocytes. In contrast to CD14 and CD11b, hormone-induced expression of the Cdk inhibitor p21 in THP-1 cells was unaffected by either wortmannin or LY294002. These findings suggest that PI 3-kinase selectively regulates D3-induced monocyte differentiation, independent of any effects on p21.

Key Words: myeloid cell, differentiation, vitamin D3, phosphatidylinositol 3-kinase


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