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J Biol Chem, Vol. 273, Issue 45, 29279-29282, November 6, 1998
From the Department of Biochemistry, University of Dundee, Scotland, United Kingdom
CAAT/enhancer-binding proteins
(C/EBPs)1 are a family of
leucine zipper transcription factors involved in the regulation of various aspects of cellular differentiation and function in multiple tissues. Six different members of the family have been isolated and
characterized (C/EBP Among the many liver-specific or liver-enriched genes whose
expression is variably regulated by members of the C/EBP family of
transcription factors are a very prominent class of genes coding for
acute phase (AP) proteins. These are plasma proteins whose levels of
expression are either positively or negatively regulated during the
acute phase of inflammation (reviewed in Ref. 2). As initially
suggested by the observation that hepatocytes are able to respond to
local tissue injury at distal sites, it has been demonstrated that a
number of cytokines and hormones are involved in the regulation of the
AP response (reviewed in Ref. 3). AP genes have been divided into two
major classes according to the pattern of responsiveness to cytokines.
For maximal induction class I genes require a combination of both
interleukin (IL)-1 and IL-6, sometimes with the additional need for
glucocorticoids. In contrast, class II genes are solely responsive to
IL-6 and related cytokines, either alone or in combination with
dexamethasone. Functional C/EBP-binding motifs (initially known as type
I IL-6-responsive elements (IL-6REs)) have been characterized on the
promoters of most class I genes (hemopexin, haptoglobin,
The activity and/or mRNA and protein levels of various C/EBP
genes are differentially modulated in response to inflammatory stimuli
and to recombinant cytokines. Indeed C/EBP Far from being liver-specific, induction of both C/EBP Studies of different promoters have assigned a predominant role
for the induction of particular genes to either C/EBP A number of different transcription factors have been reported
to be able to physically and functionally interact with C/EBP members
and in particular with C/EBP The availability of mouse strains in which the genes coding for
different C/EBP members have been inactivated provided a model to test
the relative importance of their different functions in the
inflammatory pathway as well as in numerous other systems. Sometimes in
apparent contrast with expectations it has certainly taught us a lesson
about the dramatic oversimplification of extrapolating from a tissue
culture plate to a living organism.
Acute Phase Genes--
Analysis of AP mRNAs in
C/EBP Cytokine Genes--
More puzzling are the results of the analysis
of cytokine gene expression in the different C/EBP mutant mice.
Induction of serum IL-6 was unchanged in C/EBP C/EBP Isoforms Coordinate the Differentiation and Function of
Myelomonocytic Cells--
Perhaps the most striking picture emerging
from the analysis of different knock-out mice in the field of
inflammation and immunity is that of a coordinated role of different
C/EBP family members in regulating the differentiation and function of
cells of the myelomonocytic lineage. Several lines of evidence
suggested an important role of the various C/EBP isoforms in
myelomonocytic cells. The expression of C/EBP
Remarkably in agreement with these findings, mice in which the
genes encoding C/EBP
C/EBP
In contrast, C/EBP As has often been the case with gene-targeting experiments, the
generation and analysis of single C/EBP knock-out mice, although confirming the importance of different family members in regulating various aspects of inflammation and immunity, have on the other hand
revealed new layers of complexity that will require more systematic
studies of gene expression in the different C/EBP-deficient strains and
in multiple mutant strains lacking more than one family member.
However, it has already clearly emerged that the relative role of
different C/EBP isoforms in regulating the expression of distinct
classes of genes may vary according not only to the cell type but also
to the quality and quantity of the signal, being determined by specific
promoter architecture and by interactions with other transcription
factors. Moreover, because members of the C/EBP family do play
important roles in inflammation by regulating the functions of both
cytokine-producing effector cells (macrophages and granulocytes) and
target cells (hepatocytes), the cell specificity of the observed
phenotypes is not always clear. The tissue-specific inactivation of
different C/EBP genes either in the liver on in different
myelomonocytic lineages would allow a more precise dissection of their
specific functions in each cell type. Finally, it appears that the main
function of C/EBP factors in myelomonocytic cells is that of
determining differentiation and expression of specialized functions,
thus suggesting that C/EBP
INTRODUCTION
Top
Introduction
References
to 
), all sharing a strong homology in the
carboxyl-terminal domain, which carries a basic DNA-binding domain and
a leucine zipper motif. The general characteristics and patterns of
expression of the C/EBP family have been described in the first
minireview of this series (1). Here I will focus on the functions of
several C/EBP family members in regulating various aspects of
inflammation and immunity in the liver and in cells of the
myelomonocytic lineage, in vitro as well as in vivo.
Regulation of Liver Acute Phase Genes
1-acid glycoprotein, serum amyloid A1, A2, and A3,
complement C3, C-reactive protein), often in association with
IL-1-responsive NF-
B sites (see below) (4-14). In contrast, in
class II genes such as 2-macroglobulin mainly type II
IL-6REs, which bind the cytokine-inducible transcription factors Stat3
and Stat1 (reviewed in Ref. 15), have been identified. Type II IL-6REs
are also found in promoters of class I genes.
, the second C/EBP family
member to be isolated, was originally identified thanks to its
inducibility by IL-6 or by IL-1 in human hepatoma cells and in a
glioblastoma cell line, respectively (16, 17). It has been subsequently
determined by many independent studies that both C/EBP and -
are
strongly up-regulated at the transcriptional level by inflammatory
stimuli such as turpentine oil and bacterial lipopolysaccharide and by
recombinant cytokines such as IL-6, IL-1, and TNF- (reviewed in Ref.
18). Conversely, C/EBP is slightly down-regulated under the same
conditions (19). Studies of the interplay of different C/EBP factors on
the promoters of several AP genes in hepatocytes have shown that at
steady state, the majority of DNA-protein complexes contain various
forms of C/EBP homodimers and C/EBP/C/EBP heterodimers (20).
Upon AP induction, however, the amount of complexes containing C/EBP is dramatically reduced, replaced by C/EBP and C/EBP, although the exact composition of these complexes varies in the different experimental systems (6-9, 21, 22). Although C/EBP mRNA and
protein levels are almost undetectable under uninduced conditions, C/EBP is relatively abundant in several tissues, including the liver, even before induction. C/EBP is known to undergo a series of
post-translational modifications that modulate its activity. The first
suggestion that induced post-translational modifications can increase
the transcriptional activating potential of C/EBP came from studies
on Hep3B cells, in which transfected C/EBP was able to induce
transcription of a reporter gene much more efficiently in the presence
of IL-6 (16). Subsequently, several phosphorylation sites have been
demonstrated on this protein. Phosphorylation of serine 276 has been
shown to take place in a pituitary cell line in response to
intracellular Ca2+ increase via a
calcium/calmodulin-dependent kinase (23); activation of the
protein kinase C pathway causes phosphorylation of Ser-105 in HepG2
cells (24). Finally, activation of mitogen-activated protein kinase
following induction of the Ras pathway leads to phosphorylation of
Thr-235 (25). Although all these events lead to increased
transactivating potency of C/EBP, only the last one can be linked to
IL-6 signaling. In contrast, the C/EBP-dependent activation of target AP genes is considered to be solely secondary to
transcriptional activation of its gene. Accordingly, ectopical expression of C/EBP in hepatoma cells is sufficient to transactivate responsive promoters in a cytokine-independent manner (21).
Regulation of Other Genes Involved in Inflammation
and -
levels by inflammatory stimuli occurs in most tissues analyzed, thus
suggesting a more general role of these two factors in inflammation (17, 26). Notably, expression of various C/EBP isoforms is differentially induced during macrophage and/or granulocyte
differentiation. C/EBP-binding motifs have been identified in the
functional regulatory regions of various genes expressed by cells of
the myelomonocytic lineages, including those encoding the inflammatory
cytokines IL-6, IL-1, and TNF- (17, 27-29), other cytokines such
as IL-8 and IL-12 (30, 31), genes encoding proteins important for macrophagic or granulocytic functions such as inducible nitric oxide
synthase (32), lysozyme (33), myeloperoxidase (34), and neutrophil
elastase (35), the gene encoding the granulocyte colony-stimulating
factor (G-CSF) (36), and the macrophage, granulocyte, and
granulocyte-macrophage receptor genes (37). Interestingly, C/EBP sites
are also present on several viral promoters (38-43). Of particular
relevance in this context is the finding that C/EBP sites are
specifically required for replication of the human immunodeficiency
virus-1 in macrophages but not in CD4+ cells (44). However,
due to the complexity of the C/EBP family and to the co-expression of
several family members in the same cell, the relative role of each
C/EBP isoform in the regulation of all these genes is still unclear.
Interactions with Other Transcription Factors
or C/EBP
(6-9, 21, 22). Although this may be partly because of different
experimental conditions, it is also likely to reflect physiological differences due to promoter context, to the relative affinity of specific sites for C/EBP proteins, and to the interactions with other transcriptional activators or co-activators. It is also
interesting to note that different promoters all containing C/EBP
binding sites can undergo completely divergent regulation. For example,
the negative AP reactant mouse albumin gene carries various high
affinity C/EBP motifs in its promoter, but its expression is very high
at steady state and is down-regulated by IL-6 (45); in contrast the
human C-reactive protein promoter, with two weak C/EBP sites, is poorly
expressed at the steady state but is stimulated by IL-6 (10). Clearly,
the specific composition of these two promoters and the participation
of different non-C/EBP factors in their complex regulation can
partially explain this apparent paradox. On the other hand, the
specific transactivating capacities of the different C/EBP polypeptides
are also likely to play an important role. C/EBP is for example a
stronger transcriptional activator than C/EBP (16); moreover, both
C/EBP and C/EBP mRNAs can give origin to truncated forms that
can act either as inhibitors or as weak activators (20, 46). In
vivo, many different combinations in either homodimeric or
heterodimeric forms are possible, giving rise to multiple polypeptides
with distinct physiological properties whose differential occupancy of
promoters may be dictated by their relative abundance and affinity and
by protein-protein interactions with other factors binding to adjacent sites.
. Among those, the interactions with
members of the NF-B family of transcription factors (47, 48) are
particularly intriguing because they link the pathways of two major
mediators of inflammation, IL-1 and IL-6. Interestingly, adjacent C/EBP
and NF-B motifs are found in the promoters of many AP class I genes
that require both IL-1 and IL-6 for their induction, as well as those
of several cytokine genes, suggesting that cooperative interaction
between the two families of transcription factors may represent a
general mechanism of coordinating transcriptional responses to selected
stimuli. Indeed, synergistic activation by C/EBP and NF-B members
has been demonstrated for the genes encoding the acute phase proteins
serum amyloid A1, A2, A3, and 1-acid glycoprotein, as
well as the cytokines IL-6, IL-8, and IL-12 and the G-CSF (11-13, 30,
31, 36, 49, 50). Cooperativity between the two families of
transcription factors has also been demonstrated in the case of the
human immunodeficiency virus long terminal repeat (43). C/EBP and
NF-B interactions have also been shown to lead to antagonistic
effects (47, 51), again suggesting that promoter architecture and
specific cell type are likely to play a major role. Although the
mechanisms responsible for cooperative effects have not yet been
entirely clarified, productive interaction requires the integrity of
both the NF-B rel homology domain and the C/EBP leucine
zipper motif (48). Increased affinity of C/EBP and NF-B for their
respective sites has been demonstrated (43, 47), and DNA-protein
complexes containing both proteins have been detected using both
NF-B and C/EBP sites (11, 43, 50).
A Lesson from Life
-deficient mice has shown that not all AP genes thought to
require C/EBP for their induction are in fact equally regulated by
this factor (52); indeed, induction of both hemopexin and haptoglobin
mRNAs was normal in the C/EBP
/ mice, whereas induction of
serum amyloid A and P mRNAs was reduced and induction of C3 was
totally impaired, at least at the protein level. The most prominent
role of C/EBP in the transcriptional regulation of the serum amyloid
A, serum amyloid P, and 1-acid glycoprotein genes
appeared to be the maintenance of the induced state rather than the
initial induction; after an initial accumulation comparable with that
of the wild type mice, the mRNA levels for these three genes
started to decrease in the C/EBP/ mice, dropping at almost
background levels by 24 h, the time point at which the wild type
mice reached (in contrast) their peak. Because induction of both
C/EBP and C/EBP mRNAs occurs relatively late after the inflammatory stimulus,2 it is
likely that transcription factors like NF-B and Stat3, whose
activation is much faster but transient, are responsible for the first
burst of induction, being partly replaced after a few hours by
C/EBP members. In agreement with this idea, it has been recently
demonstrated that Stat3 is involved in the IL-6-induced up-regulation
of both C/EBP and C/EBP gene promoters (53). This suggests a
sequential model in which the induction of inflammatory cytokines such
as IL-1 and IL-6 in response to inflammatory stimuli would first
trigger the activation of pre-existing, inactive forms of Stat3
and NF-B (illustrated in the upper part of
Fig. 1, early inflammation). These
factors would in turn initiate the activation of both class I and class
II genes although at the same time Stat3 would induce new synthesis of
both C/EBP and C/EBP. The pre-existing population of C/EBP
molecules, activated by phosphorylation, would also participate in this
initial induction of acute phase genes by interacting with NF-B.
However, the main role played by C/EBP factors in the induction of AP
genes is linked to the synthesis of new C/EBP and polypeptides,
which will substitute for the early factors NF-B and Stat3, thus
allowing the activated status of AP genes to be maintained
(lower part of Fig. 1, late inflammation).
According to this model, C/EBP is likely to act even at a later
stage in the induction of AP genes, and its induction, which appears to
be normal in C/EBP-deficient mice,2 is likely to
partially compensate for the absence of C/EBP. Late induction of AP
genes should therefore be severely impaired in mice lacking both
C/EBP and -. This double mutant mouse strain has been recently
generated (54), but no information is available about regulation of the
AP response. C/EBP-deficient mice die shortly after birth (55),
preventing an analysis of the liver AP response. Although
liver-specific inactivation of the C/EBP gene was recently described
(56), no information is available on the regulation of the AP response
in these mice.
View larger version (34K):
[in a new window]
Fig. 1.
Sequential model of induction for acute phase
genes. Inflammatory stimuli induce the production of circulating
cytokines (mainly IL-6, IL-1 , and TNF-). Both TNF- and IL-1
are known to trigger nuclear translocation of NF-B and activation of
the Ras pathway, as well as transcriptional induction of C/EBP and
C/EBP (whose mechanism is still unknown), whereas IL-6 mediates
activation of Stat3 and of the Ras pathway, which ultimately leads to
phosphorylation and activation of C/EBP. This wave of
post-translational activation of pre-existing transcription factors
triggers the early induction of responsive AP genes. At the same time
activated Stat3 also induces transcription of the C/EBP and -
genes. The newly synthesized C/EBPs bind in different combinations to
the AP gene promoters, either functionally replacing the other factors
or synergizing with them depending on promoter composition and duration
of the stimulus, thus maintaining the induced state. This scheme only
illustrates a model proposed for the coordinated role of the
transcription factors NF-B, Stat3, and C/EBP and - in the
induction of AP genes and is not meant as an exhaustive description of
all possible activators of these factors. MAPK, mitogen-activated
protein kinase; MEK, mitogen-activated protein kinase kinase; JAK,
Janus family tyrosine kinase.
-deficient mice,
whereas serum TNF- induction was impaired, indirectly suggesting a
more important role for the factor in the control of the TNF- than
of the IL-6 gene (52). Among all the cytokines thought to be regulated
by C/EBP, only G-CSF mRNA induction is impaired in peritoneal
macrophages from C/EBP/ mice (57). Notably, IL-6 serum levels
were elevated in aging C/EBP/ mice (58, 59), further suggesting
that this factor is totally dispensable for IL-6 gene activity. No defects in cytokine production have been detected in macrophages from
C/EBP-deficient mice.3
Interestingly, although cytokine gene expression has not been analyzed
in C/EBP-deficient mice, G-CSF receptor mRNA is almost undetectable in their liver (60). In contrast, inactivation of the gene
encoding C/EBP
, a recently isolated family member specifically
expressed in cells of the myelomonocytic lineages (61, 62), results in
decreased levels of several cytokine mRNAs (interferon-
,
TNF-, IL-2, IL-4, and IL-12 p40) in the spleen (63). Unfortunately,
neither the inducibility of these cytokines nor the levels of IL-6,
IL-1, G-CSF, granulocyte-macrophage CSF, or macrophage CSF have been
analyzed yet in the C/EBP mice.
, -, and - is
differentially regulated in myelomonocytic cell lines (64, 65).
In vivo, C/EBP expression is relatively high in immature
granulocytic cells but is down-regulated in most mature granulocytes
(65), and C/EBP is preferentially expressed during granulocytic
differentiation both in cell lines and in human primary
CD34+ cells (61, 62). Moreover, as already mentioned, C/EBP
family members can specifically transactivate the promoters of several myeloid-specific genes, and the chicken homologue of C/EBP, NF-M, is
a myeloid-specific factor mediating eosinophils differentiation (66).
, -, and - have been inactivated show specific defects in either macrophagic (C/EBP) or granulocytic (C/EBP and C/EBP) differentiation and/or functions (see below). In contrast, no abnormality was detected in C/EBP-deficient mice.
appears to play an important role in determining
activation and/or terminal differentiation of macrophages. Indeed, C/EBP-deficient mice developed a lymphoproliferative disorder that
can be linked to defects in macrophagic activation, as suggested by
defective nitric oxide (NO) production by splenic macrophages and by
the observation that no active IL-12, normally produced by activated
macrophages, could be detected in the serum of the mutant mice infected
with Candida albicans (58, 59). Macrophages from
C/EBP-deficient mice were also defective in intracellular killing of
Listeria monocytogenes and displayed impaired tumoricidal and tumoristatic activity (57). The peritoneal macrophages used for
these studies were able to produce normal amounts of NO, which is
thought to play an important role in the elimination of intracellular bacteria and parasites (67), thus suggesting that a NO-independent, C/EBP-dependent pathway may be involved in
Listeria killing and tumoricidal activity. Mainly as a
result of these specific defects in macrophage functions, the
C/EBP/ mice are extremely susceptible to infections with
microorganisms such as C. albicans and Listeria. No specific defects related to granulocytic differentiation or activation have been detected in these mice, although no direct tests
have been performed.
and C/EBP seem to play a crucial role
in specific stages of granulocytic differentiation. C/EBP-deficient mice (55) were strikingly found to totally and selectively lack mature granulocytes (60), probably as a result of a specific maturational block of myeloid precursors toward mature neutrophils and
eosinophils. This defect appears to be intrinsic to the hematopoietic precursor cells, and the loss of granulocytic maturation correlated with loss of expression of G-CSF receptor in the liver. However, the
observation that mice in which the gene encoding G-CSF receptor has
been inactivated still can form mature neutrophils (68) suggests that
other still unidentified critical targets of C/EBP must exist that
make this factor essential for granulocytic differentiation. In
agreement with these findings, it has been recently shown that conditional expression of C/EBP in bipotential myeloid progenitors is sufficient to trigger neutrophilic differentiation (69). Unfortunately, analysis of the immune functions of the C/EBP/ mice was not possible because the mutation caused perinatal death (55).
In contrast to the complete maturational block toward granulocytic
cells observed in the C/EBP/ mice, mice deficient in C/EBP
displayed only slightly reduced numbers of eosinophils and high numbers
of granulocytes, which were, however, morphologically atypical and not
fully functional, as suggested by a defective oxidative burst (63). In
agreement with defective granulocytic function, these mice succumbed to
opportunistic infections between 2 and 5 months of age, presenting
various infection-related tissue lesions. In conclusion, although
C/EBP appears to act as a main differentiative switch toward the
granulocytic lineage, the main function played by C/EBP in
regulating granulocytic functions appears to be specular to the
function of C/EBP in macrophages, that is the specification of
specialized functions and of terminal differentiation.
Conclusions
, -, and --deficient mice will be
precious tools to study the regulation of myeloid cells differentiation
at the transcriptional level.
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ACKNOWLEDGEMENTS |
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I thank Drs. Gennaro Ciliberto and Paul R. Crocker for critically reading the manuscript, Dr. Richard Hanson for launching and nursing this much needed minireview series, and Janice Walker for secretarial help. I am also grateful to Dr. S. Akira for sharing unpublished results and for a long standing and stimulating competition, to all members of my laboratory for their patience with me while writing, and to the Wellcome Trust for supporting my research.
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FOOTNOTES |
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* This minireview will be reprinted in the 1998 Minireview Compendium, which will be available in December, 1998. This is the second article of five in the "Biological Roles of the Isoforms of C/EBP Minireview Series."
To whom correspondence should be addressed: Dept. of
Biochemistry, University of Dundee, MSI/WTB Complex, Dow St., Dundee, DD1 5EH, Scotland, U.K. Tel.: 44-1382-345787; Fax:
44-1382-345783; E-mail: vpoli{at}bad.dundee.ac.uk.
The abbreviations used are: C/EBP, CAAT/enhancer-binding protein; AP, acute phase; IL, interleukin; IL-6RE, IL-6-responsive element; TNF, tumor necrosis factor; G-CSF, granulocyte colony-stimulating factor.
2 V. Poli, unpublished observation.
3 S. Akira, personal communication.
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Introduction
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N. Takabatake, Y. Shibata, S. Abe, T. Wada, J.-i. Machiya, A. Igarashi, Y. Tokairin, G. Ji, H. Sato, M. Sata, et al. A Single Nucleotide Polymorphism in the CCL1 Gene Predicts Acute Exacerbations in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 15, 2006; 174(8): 875 - 885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Venteclef, J. C. Smith, B. Goodwin, and P. Delerive Liver receptor homolog 1 is a negative regulator of the hepatic acute-phase response. Mol. Cell. Biol., September 1, 2006; 26(18): 6799 - 6807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Y. Suh, Y. Jin, |
