(Journal of Leukocyte Biology. 2001;69:3-10.)
© 2001
by Society for Leukocyte Biology
MAP kinase activation in macrophages
K. Murali Krishna Rao
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia
Correspondence: K. Murali Krishna Rao, M.D., Box 2015, PPRB/HELD/NIOSH, 1095 Willowdale Road, Morgantown, WV 26505. E-mail:
mir8{at}cdc.gov
 |
ABSTRACT
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Stimulation of macrophages by a variety of agents causes activation of
mitogen-activated protein kinases (MAPKs). Activation of MAPKs by
lipopolysaccharide involves CD14 and Toll receptors. Subsequent steps
still remain to be explored. Tumor necrosis factor-
(TNF-)-induced activation of MAPKs has been shown to involve the
death domain proteins (TRADD, FADD, MADD) and TRAFs. Other molecules
involved in this pathway include the protein kinases, ASK1, germinal
center kinase (GCK), hematopoietic progenitor kinase 1 (HPK1), and
GCK-related kinase (GCKR). Although, these pathways have been described
in various cell types, their role in macrophages remains to be
established. The availability of knockout mice and constitutively
active and dominant-negative mutants of MAPKs should greatly enhance
our understanding of this field. The activation of MAPKs seems to be
different in cell lines compared with primary cells. Among the
macrophages, cells from different compartments show different
expression of receptors and signal transduction molecules. These
differences may account for differences in MAPK activation and other
phenotypic differences in macrophages from different compartments.
Therefore, it is important to use primary cells for studying MAPK
signal-transduction pathways, and the data from cell lines should not
be extrapolated to primary cells.
Key Words: Toll • TNF • TRAF • CD14 • GCK
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INTRODUCTION
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In the last few years, the importance of mitogen-activated protein
kinases (MAPKs) in mammalian cell biology has been established in
innumerable studies using a wide variety of model systems. This field
has been covered in several excellent reviews [1
2
3
4
].
This review is focused on the role of MAPKs in macrophage physiology.
MAPKs constitute more than a dozen proteins belonging to three
families, extracellular signal-regulated kinases (ERKs), p38 MAPKs, and
c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs)
[1
2
3
4
]. All three families of MAPKs have been shown to
be activated in macrophages using a variety of stimuli (Table 1
). A large number of these studies have been conducted in
macrophage cell lines, yielding results much different from experiments
conducted in primary cells. In this review, an attempt will be made to
sort out these complexities and organize the current knowledge into
some patterns that might make it easier to interpret the results.
|
THE ROLE OF CELL TYPE IN EXPERIMENTAL STUDIES
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The experimental work in macrophages is conducted in a variety of
cell lines of murine or human origin. These investigations revealed
considerable differences in responses to stimuli between primary cells
and different cell lines. Lipopolysaccharide (LPS) treatment induces
activation of cytosolic phospholipase-2 (PLA2) in RAW 264.7 cells (a
mouse monocytic cell line) but not in P338D1 cells (a mouse macrophage
cell line). In particular, with respect to MAPKs, LPS stimulation
causes activation of ERK in RAW 264.7 cells but not in P388D1 cells
[39
]. Similar differences are found between different
cell lines in other kinase cascade systems, such as
phosphatidylinositol-3 kinase (PI-3-kinase) and p70S6
kinase. Inhibition of DNA synthesis by rapamycin in bone marrow-derived
macrophages (BMM) is much less than that observed in a
colony-stimulating factor type 1 (CSF-1)-dependent cell line, BAC1.2F5
(a mouse macrophage cell line) [40
].
In addition to differences between cell lines and primary cells,
considerable differences exist among the circulating monocytes and
macrophages, and among the macrophages residing in different tissues.
The circulating monocyte possesses a markedly different functional
phenotype relative to the tissue macrophage. The adhesive interactions
encountered by the monocyte, en route to the inflammatory focus,
generate signals that culminate in the expression of a proinflammatory
phenotype marked by enhanced cytokine production. The process of
adherence activates ERK1/2 and potentiates LPS-induced tumor necrosis
factor- (TNF-) production. The adherence-dependent activation of
ERK1/2 appears to be modulated by calcium/calmodulin-dependent protein
kinase IV [41
]. Another important modulator of
macrophage function, RON receptor tyrosine kinase, is expressed
in resident peritoneal macrophages but not in circulating monocytes or
alveolar macrophages [42
, 43
]. Activation
of RON inhibits LPS and interferon (IFN)-
-induced macrophage
inducible nitric oxide synthase (iNOS) production and iNOS mRNA
accumulation [44
]. Obviously, such an effect will not be
demonstrable in circulating monocytes and alveolar macrophages, the
cell types that do not express RON receptor.
Also, differences in interleukin (IL)-1ß regulation have been
demonstrated between monocytes and macrophages [45
].
Other studies have demonstrated differences in signaling pathways based
on the maturation stage of macrophages [46
]. A variety
of differences have been defined between human peripheral blood
monocytes and alveolar macrophages [47
48
49
50
]. Therefore,
the use of the generic term macrophage in studies involving signal
transduction pathways may lead to confusion. So in this review, effort
is devoted to specifying the macrophage cell type that has been used.
Such practice may aid in clarifying the results from various studies.
The most commonly used stimuli to study MAPKs activation in macrophages
are the bacterial cell wall LPS and the proinflammatory cytokine
TNF-. LPS has been shown to activate all three families of MAPKs in
a variety of macrophage cell types [9
, 11
,
14
, 32
, 34
, 35
].
Similarly, all three MAPKs have been implicated in the macrophage
activation induced by TNF- [21
, 51
,
52
].
|
SIGNAL TRANSDUCTION EVENTS ASSOCIATED WITH MAPKs ACTIVATION
WITH LPS STIMULATION
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Despite several studies using LPS, the signal transduction events
utilized by this bacterial product remain to be defined (Fig. 1
). Various pathways of activation following LPS stimulation have
been reviewed previously [53
]. LPS first interacts with
a plasma protein, LPS-binding protein, and is presented to a surface
receptor, CD14, which facilitates LPS signaling [54
]. In
addition to CD14, a second set of receptors, Toll-like receptors
(TLRs), have been shown to transduce bacterial cell wall-induced signal
transduction in macrophages [55
, 56
]. TLRs
are mammalian homologues of Drosophila Toll receptor and are
thought to have a role in innate immunity [55
,
57
]. TLRs have been demonstrated in human monocytes
[58
] and mouse peritoneal macrophages
[59
]. TLR4 is identified now as the signaling receptor
for LPS [60
61
62
]. Association of LTR 4 with another
molecule, MD-2, is required for LPS recognition [59
].
This association with MD-2 is essential for activation of MAPKs and
phosphorylation of the transcription factor Elk-1 [63
].
A role for Toll receptors in MAPK activation is demonstrated further by
the observation that ectopic expression of hToll (TLR4) in human
embryonic 293 cells causes activation of JNK/SAPK [58
].
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Figure 1. A schematic representation of the molecules implicated in MAPK
activation in cells of macrophage/monocyte origin following LPS
stimulation.
|
|
LPS has been shown to activate protein kinase C (PKC) in macrophages
[64
]. In human monocytes, the protein kinase C-zeta
isoform seems to be activated through a PI-3-kinase-dependent pathway
[65
]. PKC in turn has been shown to activate MAPK
pathway in a manner independent of Ras but dependent on Raf
[66
]. Further evidence for involvement of PKC in MAPK
activation is provided by the fact that defective LPS-dependent ERK1/2
activation in endotoxin-tolerant mice can be reversed by direct PKC
stimulation [67
]. In human alveolar macrophages,
activation of phosphatidylcholine-specific phospholipase C (PC-PLC)
induced by LPS has been linked to activation of ERK1/2
[5
]. Other pathways that have been implicated in ERK
activation by LPS include ras and Raf-1-mediated events
[68
69
70
]. Another pathway for LPS action is the
activation of sphingomyelinase to release ceramide, which then
activates ceramide-activated protein kinase (CAK). Raf-1 is a target
for CAK, providing an entry into the MAPK pathway [71
].
Although the exact pathways for activation of MAPKs in macrophages
following LPS stimulation still need to be defined, clearly CD14 and
TLR-mediated events are involved in the process.
|
SIGNAL TRANSDUCTION EVENTS ASSOCIATED WITH MAPK ACTIVATION WITH
TNF- STIMULATION
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TNF- binds to two distinct TNF receptors of 55 kD (TNFR1) and
75 kD (TNFR2) (reviewed in [72
]; Fig. 2
). Binding TNF- to its receptor initiates association of a
number of TNF receptor-associated proteins to the cytoplasmic end of
TNF receptors. These include TNFR1-associated death domain protein
(TRADD), which recruits Fas-associated death domain (FADD, also known
as MORT1) protein and TNF receptor-associated factor 2 (TRAF2)
[72
, 73
]. TRAF2 contains a conserved
C-termial region termed the TRAF domain, which interacts with TRADD and
an N-terminal ring finger required for signaling the activation of
nuclear factor-
B (NF-B) and JNK/SAPK [74
75
76
].
Another step in the activation of JNK/SAPK through TRAF2 is involvement
of the apoptosis signal-regulated kinase 1 (ASK1) [77
].
A third death domain-containing protein, MAP kinase-activating death
domain protein (MADD), has been shown to activate ERK in a specific
manner [78
]. However, all these observations have been
made in different cell types, other than macrophages, and their
relevance to macrophage function remains to be established. It has been
shown that activation of SAPK also involves three other protein
kinases, germinal center kinase (GCK) [79
,
80
], hematopoietic progenitor kinase 1 (HPK1)
[81
, 82
], and GCK-related kinase (GCKR)
[83
]. HPK1 has a limited range of tissue expression,
whereas GCK, although widely expressed, is only affected marginally by
TNF [80
]. GCKR is widely distributed and is activated by
TNF [83
, 84
]. Evaluating the presence and
activation of these kinases in macrophages from different compartments
may prove useful in understanding the molecular basis for differences
in macrophages from different sources.
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Figure 2. A composite schematic representation of the various molecules
implicated in MAPK activation in different cell types following TNF
stimulation. The roles of many of the molecules in monocyte/macrophage
cell activation remain to be established.
|
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ROLE OF MAPKs IN MACROPHAGE DIFFERENTIATION AND PROLIFERATION
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Activation of MAPKs has been demonstrated with agents that induce
proliferation and activation. BMM proliferate in response to specific
growth factors, such as colony-stimulating factor-1 (CSF-1, also called
M-CSF). CSF-1 is required for the development of monocytes/macrophages
from progenitor cells and for the survival and activation of mature
macrophages. CSF-1 activates MAPKs in BMM [19
,
22
23
24
]. Furthermore, when cells are stimulated with
activating factors, such as LPS, macrophages stop proliferating and
produce proinflammatory cytokines. However, both types of stimuli
induce activation of ERK. Differences in the time and duration of ERK
activation have been proposed as mechanisms for distinguishing between
pathways directed toward proliferation versus activation
[22
]. The termination of ERK activity may be a result of
simultaneous transient expression of mitogen-activated protein kinase
phosphatase-1 (MKP-1), which correlates with the inactivation of ERK1/2
[85
]. A role for MAPKs in the regulation of cell
proliferation is supported by the observation that ERK and p38
participate in the regulation of D-type cyclins, which are essential
and rate-limiting for G1-phase progression in normal mammalian cells
[86
]. However, other investigators question if ERK
activation is absolutely required for macrophage proliferation
[19
]. Evidence supporting a role for MAPKs in macrophage
differentiation comes from studies in promyelocytic cell lines, HL-60
and U937. Treatment of HL-60 cells with phorbol 12-myristate 13-acetate
(PMA) results in growth arrest and differentiation toward the
macrophage lineage [7
]. PMA causes rapid activation of
ERKs, and this activation is believed to be essential for PMA-induced
differentiation of HL-60 cells. PMA induces the expression of
cyclin-dependent kinase inhibitors, p21(WAF) and p27(kip1), which are
modulated by an inhibitor of the ERK cascade (PD 98059). This was taken
to mean that a link exists between ERK activation and p21(WAF) and
p27(kip1) induction in the process of terminal differentiation
[7
]. ERK has also been implicated in PMA-induced
differentiation of U937 cells (a human monoblastoid leukemia cell
line), where it has been shown to phosphorylate a TATA-binding protein
and thereby induce gene transcription leading to macrophage
differentiation [17
]. However, a PMA-resistant variant
of the U937 cell line (UT16) shows activation of PKC, Raf-1, and
ERK/MAP kinases similar to parental cell line but fails to
differentiate into a monocytic cell lineage [87
]. Recent
observations indicate that prolonged activation of mitogen-activated
protein kinase pathway is required for macrophage-like differentiation
of a human myeloid leukemic cell line [88
]. Other
studies indicate that activation of p38 may lead to apoptosis or cell
activation, depending on what other factors, such as ERK1, activator
protein-1 (AP-1), and NF-B, activate coordinately
[89
]. Clearly, the regulation of cell proliferation is
more complicated than simply activation of MAPKs. CSF-1 causes
increased expression of protein phosphatase-2A (PP2A) in BMM, and
inhibition of PPA2 with okadaic acid prevents DNA synthesis in a
dose-dependent manner [23
]. Okadaic acid does not affect
the basal or CSF-1-induced ERK activity in BMM, indicating that
PPA2-dependent cell proliferation could be dissociated from ERK
activation in macrophages [23
]. Therefore, it is
reasonable to assume that a series of events have to take place for the
final emergence of a phenotype and several checks and balances exist,
which finely regulate the response to a given agent.
|
DEVELOPMENTAL CHANGES IN MAPKs IN MACROPHAGES
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Four isoforms of p38 MAPK (p38, ß, , 
) have been
described. In monocytes, p38 is the predominant form, expression of
p38 is low, and p38ß is not detected. In macrophages, p38 and
p38 are abundant, but p38ß is absent. It is suggested that p38
plays a major role in the inflammatory response [90
].
Other investigators, however, show a coordinate activation of all four
endogenous p38 isoforms and consider all may play an important role in
inflammation [91
].
Further understanding of the role of MAPKs in macrophage
differentiation and proliferation is being gained by studying the
embryonic stem cells. Suppression of the protein tyrosine phosphatase
SHP-2 and ERK signaling has been shown to promote self-renewal in mouse
embryonic stem cells [92
]. Many mouse gene knockout
models are being developed, and even though some of the genetic
disruptions of MAPK pathways lead to embryonic lethal mutants, stem
cells from the embryos are being used to study the role of MAPKs in
various developmental processes [93
, 94
].
|
CONSEQUENCES OF MAPKs ACTIVATION
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After phosphorylation and activation, the MAPKs translocate to the
nucleus where they phosphorylate and activate several targets.
Transcription factors are the major targets for MAPKs. The
transcription factors phosphorylated include ELK1 [95
,
96
], ATF-2 [97
], and c-Jun
[98
], and they in turn induce transcription of several
early genes involved in cell activation, proliferation, and
transformation. MAPKs have been recognized generally for their role in
mediating signal-transduction events regulating transcription, but
recent studies implicate them in the regulation of translational events
also [99
]. The eukaryotic initiation factor, eIF4E, is
phosphorylated by MAPKs [100
]. Specifically, the p38
MAPK inhibitor, SB 203580, blocks the phosphorylation eIF4E
[101
]. It needs to be emphasized that several
proinflammatory mediators are under transcriptional as well as
translational control; these include NO [102
], TNF
[99
], and IL-ß [103
]. Therefore, MAPKs
may be involved at transcriptional and translational regulation of
proinflammatory mediators.
|
NEWER TECHNIQUES FOR STUDYING MAPK FUNCTIONS
|
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In the past, most of the studies resorted to chemical inhibitors
for studying MAPK regulation. But, subsequent studies indicated that
the drugs employed could inhibit or activate other protein kinases
under some experimental conditions [104
,
105
]. Molecular biology techniques provide a more precise
way for activating or inhibiting specific enzyme activities. Targeted
disruption of MAPK kinases (MKKs) has been accomplished. MKK4 gene
disruption causes marked defects in JNK activation and early embryonic
death [106
107
108
]. However, stem cells from the embryos
can be used for studies of signal transduction as mentioned above.
Targeted disruption of MKK3 revealed the importance of TNF-induced
cytokine expression in fibroblasts [109
]. Defective
thymocyte maturation has been demonstrated in ERK1 knockout mice
[110
]. Such animals can be used for studying the effects
of specific MAPK gene disruptions in macrophage function.
Other strategies to study MAPK function include making constitutively
active MKKs [111
], constitutively active MAPKs by fusing
with constitutively active MKK [112
], and constitutively
activating MAPKs by overexpressing tyrosine kinases such as c-fes
[113
]. A number of vectors have been developed to
overexpress activated MAPKs or dominant-negative mutants. Such vectors
are available for JNK [114
], p38 [115
],
and ERK [116
]. These methodical advances need to be
applied to study the role of MAPKs in macrophage function and have the
potential to yield important insights into their function in this cell
type.
|
CONCLUSION
|
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As shown in Table 1
, all three MAPKs have been shown to undergo
activation in several macrophage cell types using a variety of stimuli.
MAPKs have been implicated in proliferation, differentiation, and
activation of macrophages. The response appears to be context-specific.
For example, stimulation with MCF causes phosphorylation of
MAPKs and proliferation in BMM, but stimulation with LPS in monocytes
causes phosphorylation of MAPKs, inhibits proliferation, and causes
activation. In addition, the response to stimuli depends on the
maturation state of the macrophages. This may be because of differences
in the expression of various signal-transduction molecules. For
example, the expression of PKC isoforms is different in blood monocytes
compared with alveolar macrophages [49
]. Also, human
alveolar macrophages are markedly deficient in REF-1 and
AP-1-binding activity [47
]. Differences in RON receptor
expression have been mentioned above.
Several studies indicate that all three MAPKs are activated by LPS in
macrophage cell lines such as RAW 264.7, J774.A, and NR8383 cells (see
Table 1
). But this may not be the case in primary cell lines. In human
alveolar macrophages, ERK and p38 activation have been demonstrated
[6
]; and although JNK/SAPK activation has not been
studied specifically, simultaneous inhibition of ERK and p38 kinase
pathways reduces cytokine expression to near control levels, suggesting
that JNK/SAPK pathway by itself is not sufficient for cytokine
expression [6
]. Our studies indicate that in rat
alveolar macrophages, LPS causes activation of only ERK and that
inhibition of ERK by PD 98059 abrogates NO and TNF- production
(unpublished results). In view of these observations, caution is needed
in extrapolating data from cell lines to primary cells. In fact, the
role of MAPKs in the regulation of inflammatory cytokine biosynthesis
was discovered using the cytokine-suppressive anti-inflammatory drugs
in a human monocytic cell line, THP.1. In that study, the authors
acknowledge that the cell line was more sensitive to inhibition by the
drugs than human monocytes [117
]. It should be noted
that the suppression of cytokine production by p38 MAPK inhibitors has
been shown to occur at a post-transcriptional step in this cell line.
In view of the differences enumerated in various cell types, the signal
transduction events associated with MAPK activation cannot be
extrapolated from one cell type to another. In fact, differences in
these signal transduction pathways may be the key to the phenotypic
variation among the cells of monocytic/macrophage lineage in various
compartments. Many of the signal transduction events associated with
TNF receptor activation have been demonstrated in different cell types,
and there are very few studies in macrophages specifically. Study of
the expression of various TRAFs and death domain proteins may be useful
in understanding the differences in macrophage phenotypes. These
studies should be conducted in primary cells, rather than cell lines,
to approach more closely the situations that may be valid in
vivo. The availability of knockout mice and constitutively active
and dominant-negative mutants of MAPKs should enhance our understanding
of this field greatly.
Received July 3, 2000;
revised September 17, 2000;
accepted September 22, 2000.
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ABSTRACT
INTRODUCTION
