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332 Part IV Disorders of Hematopoietic Cell Development

receptor (II/III), and the scavenger receptor. Mature monocytes, like M-CSF. Monocytes have also been demonstrated to have functional
neutrophils, show high-level expression of CD11b/CD18. Follow- G-CSF receptors, although G-CSF appears to function mainly
ing differentiation to macrophages, the cells acquire expression of to decrease monokine secretion rather than to increase monocyte
macrosialin (CD68), a glycoprotein of unknown function that may proliferation.
play a role in lipoprotein metabolism. Macrophages also express
sialoadhesin, a member of the sialic acid-binding receptor family.
Although its precise function has not been proved, sialoadhesin medi- Transcriptional Regulation of
ates binding to sialic acid moieties on cell surfaces and probably Monocyte Differentiation
plays a role in macrophage cell–cell interactions and cell–extracellular
matrix interactions. Of the several transcription factors that regulate the development of
CD14 is a major functional surface protein of the monocyte/ the monocyte/macrophage lineage, the best is PU.1 (discussed earlier),
−/−
macrophage lineage. CD14 is the receptor for lipopolysaccha- because abrogation of PU.1 expression in PU.1 mice results in
ride (LPS), leading to monocyte/macrophage activation. More perinatal lethality accompanied by the absence of mature monocytes/
recent studies have suggested that CD14 may also have a role in macrophages and B cells and delayed and reduced granulopoiesis. A
apoptosis. number of factors, the most notable of which is c-Jun, cooperate with
Monocytes contain both primary (peroxidase-positive) and PU.1 to regulate monocyte-specific genes.
secondary (peroxidase-negative) granules. The primary granules
of monocytes, like those of neutrophils, contain myeloperoxidase. c-Jun
Secondary granule fusion with the membrane on stimulation The c-jun proto-oncogene encodes the transcriptional activator
of monocytes results in upregulation of Mac1 and p150, and is protein AP-1. As a member of the early response genes, c-jun is
thought to play a role in adhesion and diapedesis of stimulated rapidly and transiently activated in response to external proliferative
monocytes. signals. The expression of c-Jun as well as related family members
JunB and JunD is upregulated during monocytic differentiation.
+
Control of Monocytopoiesis In addition, overexpression of c-Jun in M1, U937, or WEHI-B D
myeloid cell lines, as well as in myeloid progenitor cells, was found
−/−
Cytokine Regulation of Monocyte Proliferation to result in partial monocytic differentiation. However, c-Jun fetal
liver cells are capable of reconstituting hematopoiesis in syngeneic
and Differentiation recipients, suggesting that c-Jun is not required for myeloid develop-
ment. This finding may reflect a compensatory role played by other
The effects of colony-stimulating factor 1 (CSF-1, also known as Jun family proteins.
M-CSF), the primary regulator of mononuclear phagocyte produc- As discussed, c-Jun serves as a coactivator of PU.1 during macro-
tion, are thought to be mediated by the high-affinity receptor tyrosine phage development. Recent studies have revealed that downregula-
kinase CSF-1 receptor (CSF-1R). CSF-1R is encoded by the c-fms tion of c-jun by C/EBPα is necessary for granulocytic maturation
proto-oncogene. A total of five human or mouse mRNAs result from and appears to be the mechanism through which C/EBPα blocks
alternative splicing and the alternative use of the 3′ untranslated macrophage development (see Fig. 27.4). C/EBPα not only binds
region. This results in three isoforms of the CSF-1 protein: a secreted to the promoter of the c-jun gene and decreases its expression but
proteoglycan, a secreted glycoprotein, and a membrane-spanning cell also binds to PU.1, thereby inhibiting its activity. Such transcrip-
surface proteoglycan have been described. tion factor cross-talk resulting in subtle changes in the levels of
The phenotypes of Csf1-null mice and of mice harboring an transcription factors within a given lineage appears to be an emerging
op
op
inactivating mutation in the coding region of CSF-1 (Csf /Csf1 ) paradigm through which master regulators of lineage specification,
(osteopetrotic mice) are virtually identical; features include toothless- such as C/EBPα and PU.1, direct lineage-specific development by
ness, low body weight, low growth rate, and deficient tissue macro- directly upregulating lineage-specific genes as well as by blocking the
phages. In addition, the mutant mice have defects in both male and progression of alternate lineages.
female fertility. Compared with their wild-type littermates, splenic
erythroid burst-forming unit and high-proliferative-potential colony- Other Transcription Factors Modulating
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forming cell levels in both Csf1 /Csf1 and Csf1 /Csf1 mice were Monocyte Development
significantly elevated, consistent with a negative regulatory role for Egr-1. Egr-1 belongs to a family of zinc finger transcription factors,
CSF-1 in erythropoiesis and in the maintenance and proliferation and is expressed in a number of tissues and at various points in devel-
of primitive hematopoietic progenitors. The plasma CSF-1 levels opment including the terminal stages of macrophage and neutrophil
−
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in CSF receptor-null (Csf1R /Csf1R ) mice was elevated 20-fold, differentiation. Egr-1 is necessary for monocytic differentiation
in agreement with the previously reported clearance of circulating of myeloid cell lines U937 and M1 and prevents factor-induced
CSF-1 by CSF-1R-mediated endocytosis. Despite their overall simi- granulocytic differentiation of HL60 and 32Dcl3 cells. In addition,
−
−
larity, several phenotypic characteristics of the Csf1R /Csf1R mice ectopic expression of Egr-1 in myeloid BM progenitors was found
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were more severe than those of the Csf1 /Csf1 mice. The results to result in an increase in the number of CFU-M at the expense of
suggest that all of the effects of CSF-1 are mediated via the CSF-1R, CFU-G. However, mice lacking Egr-1 develop normal numbers of
but that additional effects of the CSF-1R could result from CSF-1- macrophages, a phenomenon attributed to the possible compensatory
independent activation. effects of other Egr family members.
Signaling through the CSF-1R appears to be critical for monocyte/
macrophage development. Although little is known about the events C/EBPβ. As discussed, expression of C/EBPβ increases during
that lead to stimulation of a monocyte/macrophage–specific array of myeloid maturation and has been shown to be important for
genes, it is clear that several transcription factors, probably stimulated monocyte/macrophage gene expression and development.
by M-CSF–related signaling, play vital roles in the development of
this lineage. It should be noted, however, that the ability of phorbol MafB and c-Maf. The transcription factors MafB and c-Maf
esters to induce monocytic differentiation of myeloid cell lines belong to a family of basic-leucine zipper (b-Zip) factors that bind
through activation of the protein kinases Cα and Cδ suggests a role DNA as dimers. The Maf proteins can dimerize with members
for the PKC pathway in monopoiesis. of other b-Zip family proteins including c-Jun, fos, and NF-E2
IL-3, G-CSF, and tumor necrosis factor (TNF) have all been in erythroid cells. Ectopic expression of MafB in myeloblasts
shown to synergize with M-CSF in the proliferation of macrophages. directed their expression to macrophages, whereas overexpression
G-CSF has also been shown to induce the increased release of of c-Maf in HL60 and U937 myeloid cells resulted in monocytic
monocytes; this is an indirect effect dependent on the presence of differentiation.