Phorbol esters induce differentiation of human CD34+ hemopoietic progenitors to dendritic cells: evidence for protein kinase C-mediated signaling.
The intracellular signals that mediate the differentiation of pluripotent hemopoietic progenitors to dendritic cells (DC) are largely undefined. We have found that the phorbol ester PMA by itself induced 47% +/- 8.7% of input human CD34+ hemopoietic progenitors to differentiate into cells with morphology and surface Ag phenotype characteristic of DC by day 7 of culture. Functionally, PMA-generated DC processed and presented whole soluble Ag and also induced resting T cell proliferation and Ag-specific CTL effector function. Unlike cytokine-driven DC differentiation, PMA suppressed proliferation and induced cell death (in part via apoptosis) in cells that did not differentiate to DC. The effects of PMA were blocked by inhibitors of protein kinase C activation, suggesting a central role for this signaling molecule. PMA-mediated signaling also induced expression of the RelB transcription factor, an NF-kappaB family member implicated in DC differentiation. These findings suggest that phorbol esters activate protein kinase C, which then initiates the terminal component of an intracellular signaling pathway(s) involved in the DC differentiation of CD34+ hemopoietic progenitors.
Davis
T A
TA
Immune Cell Biology Program, Stem Cell Biology Branch, Naval Medical Research Institute, Bethesda, MD 20889-5067, USA.
Saini
A A
AA
Blair
P J
PJ
Levine
B L
BL
Craighead
N
N
Harlan
D M
DM
June
C H
CH
Lee
K P
KP
D017951:Antigen Presentation / Q000187:drug effects; D018952:Antigens, CD34 / Q000378:metabolism*; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D018952:Antigens, CD34; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D014157:Transcription Factors; D051841:Transcription Factor RelB; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate