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Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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) must
be tightly regulated to facilitate appropriate responses to complex
conditions in an inflammatory focus. This study was designed to
ascertain whether uncommitted M that have been exposed to
combinations of cytokines with opposing functions develop properties
dictated by one cytokine or by cytokine mixtures. Uncommitted rat bone
marrow-derived M (BMDMs) were incubated with IFN-
, TNF-
,
TGF-ß, IL-4, IL-6, and IL-10 alone or sequentially in combinations.
After 48 h, function was assessed by nitric oxide (NO) generation,
uptake of apoptotic neutrophils, and ß-glucuronidase expression.
IFN- followed 4 h later by TNF-induced NO generation. The
pretreatment of BMDMs before IFN- priming with TNF, TGF-ß, and
IL-4 suppressed NO generation by 87%, 92%, and 85%, respectively;
IL-10 had no effect. The same cytokines administered at 4 h after
IFN priming had no effect on NO generation. The uptake of apoptotic
polymorphonuclear leukocytes was augmented by TNF (40% vs 29%
controls; p < 0.05) and decreased by IFN-,
IL-10, and IL-4. The TNF response was unaffected by subsequent
treatment with IFN-, IL-4, or IL-10. Similarly, the decreased
polymorphonuclear leukocyte uptake induced by IFN-, IL-4, or
IL-10 was unaffected by the subsequent addition of TNF.
ß-glucuronidase expression was increased by TGF-ß and decreased by
IFN-. These responses were not modified by cytokines with the
opposing function. Thus, the functional response of BMDMs to complex
mixtures of cytokines was determined by the first cytokine to which
they were exposed. Once activated, BMDMs become unresponsive to
alternative activating signals, a finding which has obvious
implications for M function in vivo. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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)3
influence almost all aspects of immunologic and inflammatory responses
and play an essential role in linking innate and acquired immune
systems (1). M ingest and destroy bacteria and other microorganisms
(2), kill virally infected and malignant cells (3), and present Ags to
T lymphocytes (4); in addition, they not only induce inflammation (5)
but also promote its resolution (6), and they have important roles in
angiogenesis (7), tissue remodeling, and repair (8). Infiltrating M
are heterogeneous primarily because they adapt to the local
microenvironment by developing sets of attributes that enable them to
perform a particular function (9). Consequently, an understanding of
the basis for M adaptation and knowledge of what controls (or
limits) the range of activities that M develop is essential for
determining how inflammation is regulated.
Injury causes a rapid increase in the number of M in a tissue; this
increase is principally due to infiltration by monocytes that then
differentiate into M, but it is also a result of local cell division
(10, 11). The properties of M within an injured site vary
according to the nature of the injury and the length of its
evolution. This principle was exemplified many years ago by
North et al. and Mackaness et al. (12, 13), who demonstrated that an
injection of thioglycolate into the peritoneal cavity caused an influx
of M that were more adhesive than resting M, released more
lysomal enzymes, but were not cytotoxic to other cells. They then
established that M infiltrating the peritoneum as part of the T
cell-mediated response to i.p. mycobacterial purified protein
derivative not only released more enzymes but was cytotoxic as
well. These and other similar experiments led to the concepts of
elicited M and M activation (14) and to the identification of
IFN- as the principal M-activating factor (15). Since then, it
has become apparent that M can be "alternatively activated," for
example by IL-4 (16), and that other M activation states exist (9).
The rapid increase in the number of cytokines and growth factors that
have been shown to modify M function has amply demonstrated the
complexity of M activation; for instance, many of the cytokines
involved are also produced by M and are likely to have autocrine
effects. Some cytokines, such as IL-2, IL-12, IL-15, and TNF, enhance
the proinflammatory properties of M, whereas others, including IL-4,
IL-13, and TGF-ß, down-regulate these properties (reviewed in 17 . Even so, the results from many studies are contradictory, either
because different concentrations of cytokines have opposing effects
(18), or possibly because of the different sources of M used. The
studies that examined the effects of single cytokines emphasize the
degree to which M function is controlled but are relatively
uninformative with regard to how cytokines interact to induce
coordinated sets of activities that enable them to perform a particular
function. This aspect of M function has been examined by Riches et
al. using murine bone marrow-derived M (BMDMs) as a model (19, 20, 21).
They showed that uncommitted BMDMs can be induced to develop
coordinated sets of nonoverlapping and mutually exclusive properties
when exposed to IFN-, TNF, or TGF-ß. Thus, BMDMs primed with
IFN- and activated with TNF generate large amounts of nitric oxide
(NO) and synthesize complement components (such as factor B of the
alternative pathway) but do not synthesize insulin-like growth factor-1
(IGF-1) or express the lysosomal hydrolase ß-glucuronidase. By
contrast, BMDMs activated with TNF without prior exposure to IFN-
synthesize IGF-1 but do not generate NO and cannot be induced to
generate NO even when subsequently exposed to IFN-. Consequently,
IFN- priming profoundly effects the M response to TNF; in fact,
the order of exposure to these two cytokines results in the development
of cells with mutually exclusive sets of properties.
The effect of IFN- and TNF on NO generation suggests that
uncommitted M might be preconditioned to a particular activity by
the first cytokine encountered. The principal purpose of this study was
to first test this hypothesis in studies using the
"antiinflammatory" cytokines IL-4, IL-6, IL-10, and TGF-ß,
because they have been reported to modulate NO generation by
IFN--primed M or M cell lines, and second by studying
the control of two other M functions, namely the uptake of apoptotic
neutrophils and the expression of ß-glucuronidase. The results show
that all three functions are modulated by the cytokines studied, and
that in each case the response is determined by the first cytokine to
which the M are exposed. Thus, IFN- priming for NO generation is
abrogated by pretreatment with IL-4, TGF-ß, or TNF; the TNF-induced
uptake of apoptotic polymorphonuclear leukocytes (PMNs) is prevented by
pretreatment with IFN-, IL-4, and IL-10; and the TGF-ß-induced
expression of ß-glucuronidase is prevented by IFN-. None of the
treatments had any effect when administered after the primary stimulus;
the first exposure inhibits the ability of BMDMs to respond to
alternative activating stimuli. These results provide a model
for the functional activation of M infiltrating an inflammatory
focus and have obvious implications for the autocrine role of cytokines
in M activation and for cytokine-based therapies.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human rTNF- was obtained from Boehringer (Ingelheim,
Germany), and human rTGF-ß, IL-10, and IL-6 were obtained from Sigma
(Dorset, U.K.). Rat rIFN- was obtained from Bradsure Biologicals
(Loughborough, U.K.). Rat rIL-4 was produced in-house as described
previously (22) using a Chinese hamster ovary cell line (22)
that was generously donated by Dr. Neil Barclay (Medical Research
Council Cellular Immunology Unit, Oxford, U.K.).
Isolation and culture of BMDMs
Rat BMDMs were obtained using a previously described technique
(20). Briefly, bone marrow cells were flushed aseptically from the
dissected femurs of male Sprague-Dawley rats with a jet of complete
medium directed through a 25-gauge needle to form a single-cell
suspension. The cells were cultured in 75-mm tissue culture flasks
(Corning Glass, Corning, NY) and adhered to plastic in DMEM
containing 2 mM glutamine, 100 U/ml penicillin/100 U/ml streptomycin,
10% heat-inactivated FCS, and 10% L929-conditioned medium as a source
of M-CSF. After 7 days in culture, the cells were carefully removed
using 1% trypsin/EDTA, dispensed into 24-well culture plates (Corning)
at a concentration of 5 x 105 cells/well, and rested
for 24 h in M-CSF-free medium before they were washed and
incubated with the cytokines. When combinations of cytokines were used,
the initial cytokine was administered 4 h before the second
cytokine; the cytokines were not removed from the medium until M
function was assessed.
Quantitation of NO synthesis
The generation of NO was estimated by assaying culture supernatants for nitrite, which is a stable reaction product of NO. Aliquots of 200 µl of each cell-free culture supernatant were incubated with 50 µl of Griess reagent (0.5% sulfanilamide and 0.05% N-(1-naphtyl)ethylenediamine dihydrochloride in 2.5% phosphoric acid) in 96-well flat-bottom tissue culture plates for 10 min at room temperature. ODs of the assay samples were subsequently measured at 540 nm using a solution of phenol red-free DMEM. In most experiments, nitrite was measured after 48 h in culture.
Assay for uptake of apoptotic neutrophils
BMDMs were transferred to 24-well plates at a density of 5
x 105 cells/well and rested for 24 h before the
medium was changed and cells were incubated with the cytokines in
various combinations. The uptake of apoptotic neutrophils was assessed
after 48 h using a microscopically quantified phagocytic assay as
described previously (23, 24). Briefly, apoptotic neutrophils were
prepared from PMNs that had been isolated from fresh, heparinized,
normal human blood by dextran sedimentation and plasma-Percoll
centrifugation. The neutrophils were aged in Teflon bags for
24 h in Iscove’s modified Dulbecco’s medium with
10% autologous platelet-rich, plasma-derived serum. More than 98% of
these cells excluded trypan blue, and apoptosis was verified by
oil-immersion light microscopy of May-Giemsa-stained cytospin
preparations as described previously (25). The apoptotic cells were
washed once in HBSS and resuspended in DMEM at a concentration of
2.5 x 106/ml. A total of 2 x 106
PMNs were added to each well and allowed to interact with the M for
30 min at 37°C in a 5% CO2 atmosphere. The wells were
washed in saline at 4°C to remove noningested PMNs, fixed with 2%
gluteraldehyde in 0.9% saline, and stained for myeloperoxidase to
identify ingested PMNs. Next, the proportion of M that had ingested
neutrophils was counted by inverted light microscopy as described
previously (25, 26). The results are expressed (as shown in Table I
and Fig. 3) as the percentage of M
in which uptake of at least one apoptotic neutrophil could be
visualized.
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ß-glucuronidase was visualized by an enzymatic staining method
in which ß-glucuronidase catalyzed the reaction of -naphtol AS-BI
ß-D-glucuronide into the red soluble-chromogenic naphtol
AS-BI-HPR complex (27). Cytospin preparations of M that had
been harvested from the 24-well tissue culture plates were fixed in a
gluteraldehyde-acetone solution, and the slides were air-dried.
Slides were then stained with ß-glucuronidase staining
solution and counterstained with methylene blue before being mounted
with aqueous medium. Slides were coded and scored according to the
following scale: 0, no staining; 1, equivocal positive staining; 2,
weak positive staining; 3, moderate positive staining; and 4, strong
positive staining. Each cell that was counted was multiplied by a
number between 0 and 4 according to its score. Numbers were added up,
and the total was divided by the number of cells that were counted in
each experiment. The score represents an overall change in the density
of staining.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effects of IFN- and TNF on NO generation by murine
BMDMs have been reported previously (20); therefore, it was
important to confirm that these cytokines had the same effect on rat
M. Adherent, 7-day BMDMs were transferred into 24-well plates
(5 x 105 M per well), left to adhere for 4 h,
washed, and then cultured for 24 h in medium without M-CSF and
other cytokines. The medium was then changed to one containing IFN-
and TNF alone and in various combinations. BMDMs incubated with 20 U/ml
of IFN- generated small amounts of NO; TNF (10 ng/ml) had no effect
(Table I
). However, priming BMDMs with IFN- for 4 h before
activation with TNF- resulted in a marked increase of nitrite
concentration. This increase was evident after 24 h and persisted
for at least 48 h. IFN- priming for NO generation was equally
affected when BMDMs were primed for various lengths of time between 4
and 24 h before activation, but a minimum of 2 h
prestimulation was required for a significant effect.
Prevention of IFN/TNF-induced NO generation by antiinflammatory cytokines
BMDMs incubated with IL-4, IL-10, or TGF-ß generated the same
amount of NO as unstimulated controls (Table I). However, preincubating
BMDMs with either IL-4 or TGF-ß for 4 h before IFN- priming
almost completely abolished NO generation. IL-4 had a partial effect
when given simultaneously with IFN- priming and caused a 50%
decrease in nitrite concentration (Fig. 1). By contrast, TGF-ß had no effect
when administered at the same time as IFN- (Fig. 2), suggesting that IL-4 had a direct
effect on IFN priming whereas TGF-ß acted indirectly. IL-4, TGF-ß,
or TNF administered for 4 h followed by incubation of the M for
48 h in cytokine-free medium did not inhibit IFN/TNF-induced NO
generation, indicating that the inhibitory effects of short exposure to
the cytokines are temporary. IL-6 partially inhibited NO generation
when BMDMs were treated for 4 h before priming; however, like
TGF-ß, IL-6 had no effect when given together with IFN- priming.
Interestingly, IL-10 had no effect on NO generation even when BMDMs
were treated 4 h before IFN priming. The differences between the
results obtained with IL-4, TGF-ß, and IL-10 are not attributable to
the doses used, because similar results were obtained over a wide
concentration range (e.g., TGF (0.1–10 ng/ml), IL-4-containing medium
(0.1–50 µl/ml), and IL-10 (1–100 ng/ml)). The observation that none
of the antiinflammatory cytokines had an effect on IFN/TNF-induced NO
generation when administered at 4 h after the M had been
exposed to IFN- is partly consistent with some studies but is also
in contrast to results that have been reported previously in peritoneal
M and in M cell lines (28, 29).
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The uptake of apoptotic neutrophils is thought to be one of the
critical steps in the resolution of acute inflammation (30); therefore,
it might be expected to be more efficient in M whose function was
reparative rather than to cause tissue destruction. For this reason, we
assessed the influence of pro- and antiinflammatory cytokines on the
uptake of apoptotic human neutrophils by uncommitted rat BMDMs. TNF
significantly increased the proportion of BMDMs that took up apoptotic
neutrophils (TNF = 40%, controls = 29%; p
< 0.005, the Student t test). By contrast, IL-4 reduced the
proportion of BMDMs that took up the neutrophils (IL-4-treated
cells = 13%; p < 0.001, the Student t
test). TGF-ß had no effect, whereas IFN- and IL-10 reduced uptake
(Table I). These observations indicate that exposing M to cytokines
before contact with apoptotic neutrophils greatly influences the
ability of M to ingest apoptotic neutrophils. When the number
of apoptotic neutrophils ingested by 100 randomly selected M in each
well was counted, the proportionate change mediated by the above
cytokines was greater than the change in the percentage of the M
that were taking up apoptotic cells (data not shown).
Experiments in which BMDMs were incubated with TNF, IL-4, IL-10, and
TGF-ß sequentially show that the first cytokine to which BMDMs are
exposed determines their ability to take up apoptotic neutrophils at
48 h poststimulation (Fig. 3). Thus,
an identical proportion of BMDMs incubated for 48 h with TNF alone
take up apoptotic neutrophils in the same manner as do BMDNs incubated
with TNF followed 4 h later by IFN, IL-4, or IL-10 (Fig. 3).
Similar results were obtained with BMDMs that had been incubated with
IFN-, IL-4, or IL-10 alone or in combination. In each instance, the
first cytokine to which the BMDMs were exposed determined the M
uptake of apoptotic neutrophils; this program was not modified by
subsequent exposure to a cytokine that had the opposite effect on
uncommitted M.
ß-glucuronidase expression of BMDMs
The experiments to determine both the influence of cytokines on NO
generation and the uptake of apoptotic neutrophils suggested that the
first exposure to a cytokine rendered M unresponsive to subsequent
differentiating signals. Therefore, a third set of experiments was
performed to ascertain whether this finding was also the case for the
TGF-ß-induced expression of the lysosomal hydrolase
ß-glucuronidase. As reported for murine BMDMs (21), TGF-ß induced a
marked increase in ß-glucuronidase expression compared with
unstimulated controls, whereas treatment with IFN/TNF decreased
expression. Incubation with IL-10 also reduced ß-glucuronidase
expression significantly, whereas neither TNF- nor IL-4 had any
effect (Table I).
The treatment of BMDMs with TGF-ß followed 4 h later by IFN-
alone or in combination with TNF resulted in ß-glucuronidase
expression that was similar to that observed in cells incubated with
TGF-ß alone. By contrast, TGF-ß administered at 4 h after IFN
resulted in a level of ß-glucuronidase expression that was similar to
that seen in cells stimulated with IFN- alone. M incubated with
IL-4 for 4 h before IFN- had similar levels of
ß-glucuronidase expression compared with cells incubated with IL-4
alone, whereas BMDMs incubated with TNF/IFN- for 4 h before
IL-4 had ß-glucuronidase expression that was similar to that observed
in cells incubated with IFN- (Fig. 4).
These data strongly support the idea that ß-glucuronidase expression
by BMDMs is dependent upon the first cytokine stimulus used.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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infiltrating infected or otherwise damaged tissues develop
coordinated, and to some extent mutually exclusive, sets of properties,
but it is not known how this process is controlled by the local
microenvironment. However, the process must be tightly regulated and
can be accounted for by two broad models of M functional activation:
either M properties could be molded by the sum of all the stimuli to
which they are exposed, or else exposure to a specific stimulus (such
as a cytokine) could commit the cell to be activated in a particular
way and render it unresponsive to alternative activating signals. Here,
we studied the responses of uncommitted BMDMs to various cytokines
alone and in combination to distinguish between these models, and our
results provide unequivocal support for the second model under the
experimental conditions used.
M function was characterized using assays for three complex
processes known to be differentially expressed in M. Cytotoxic M
generate NO that is thought to be important for the killing of infected
cells. NO generation by BMDMs requires priming with IFN- followed by
activation with TNF or LPS (20) and is reportedly modulated by IL-4,
IL-10, and TGF-ß in M cell lines and elicited peritoneal M (28, 29, 31, 32). The uptake of apoptotic neutrophils is believed to have an
important role in the resolution of inflammation and, as reported here,
is up-regulated by TNF and decreased by IFN-, IL-4, and IL-10.
ß-glucuronidase is a lysosomal hydrolase that is strongly expressed
and released in bacterial infections or when M ingest particulate
matter such as group A streptococcal cell walls, zymosan particles, or
ß-1,3-glucan; it has been shown that TGF-ß primes M to express
lysosomal hydrolases in response to particulate stimuli (21). In our
experiments, TGF-ß markedly increased ß-glucuronidase expression by
BMDMs compared with the modest amounts found in unstimulated
controls (33), and, as shown here, expression is decreased by IFN-
alone and in combination with TNF. The effect of different combinations
of cytokines on these complex functions enabled us to ascertain whether
the exposure of BMDMs to cytokines with opposing functions resulted in
a polarized responses or an aggregated one.
In every case, the response of the BMDMs was determined by the first
cytokine to which they were exposed. Thus, NO generation was observed
only when BMDMs were first exposed to IFN- and could be prevented
completely if the M were pretreated with IL-4, TNF, or TGF-ß.
Similarly, an increased uptake of apoptotic neutrophils was only seen
in BMDMs treated first with TNF-, and the response was not
influenced by subsequent treatment with IFN-, IL-4, or IL-10, all of
which decrease uptake when given alone. Conversely, M incubated with
IFN-, IL-10, or IL-4 before exposure to TNF behaved like cells that
had been stimulated with these cytokines alone. Preincubation with
TGF-ß before exposure to IFN/TNF resulted in ß-glucuronidase
expression that was similar to that observed in cells that were
stimulated with TGF-ß alone, and incubation with IFN/TNF before
exposure to TGF-ß resulted in expression that was similar to that
observed in cells stimulated with IFN/TNF alone. These results show
that the functional activation of uncommitted BMDMs is determined by
the first cytokine to which the cells are exposed; once the activation
process has started, M become temporarily unresponsive to
alternative stimuli.
The results imply that BMDMs have a general mechanism that prevents
them from responding to other, possibly opposing signals, once they are
committed to develop a particular attribute. The mechanisms involve at
least three signaling pathways: the Janus kinase (JAK)/STAT
pathways used by IFN, IL-4, IL-6, and IL-10 (34); the extracellular
signal-related kinase and stress-activated protein
kinase/JUN families of mitogen-activated protein kinases
that are responsible for TNF signaling (35); and the Smad family for
TGF-ß (36). This mechanism must be selective, in that not all
activities of the particular cytokines are suppressed: for example TNF
is required for the optimal generation of IFN-primed M, even though
the prior exposure of M to TNF prevents priming. Similarly, IL-10
has no effect on IFN- priming for NO generation but prevents the
effect of TNF on the uptake of apoptotic neutrophils. Lastly, the
mechanism takes at least 2 h to develop according to our results
and those of Riches et al. with regard to the effect of TNF on IFN
priming (20) and also our observations and those of others with regard
to IL-4 (29).
It is highly unlikely that inhibitory effects can be explained by
changes in the surface expression of cytokine receptors, and this
possibility was formally excluded in the case of IFN priming because
IFNRs are up-regulated by TNF (37) and only modestly decreased by IL-4
and TGF-ß (38). The direct inhibition of intracellular signaling
pathways provides the most economical explanation, and the recent
descriptions of cytokine-inducible families of inhibitors of both the
JAK/STAT (reviewed in 39 and Smad (reviewed in 36 pathways
provide potential mechanisms. The expression of JAK/STAT inhibitors,
which include cytokine-inducible Src homology 2-containing protein and
suppressor of cytokine signaling (SOCS)-1–3, are induced by a variety
of cytokines, including IFN-, TNF, and IL-4; such inhibitors
suppress signaling by inhibiting the catalytic activity of JAKs (40).
The IFN-- and IL-6-induced differentiation of murine M1 cells into
M is suppressed by the overexpression of SOCS-1 (41). TGF-ß
signals through the family of Smad proteins. Two inhibitory Smads
(Smad6 and Smad7) have recently been described (42, 43), but less is
known about what stimulates their expression. However, Kretzschmar et
al. have recently shown that activation of the extracellular
signal-related kinase pathway causes the phosphorylation of
Smad4, which inhibits its activity by preventing translocation to the
nucleus (44). It is not known whether SOCS family members and
inhibitory Smads affect the differentiation of BMDMs, but we are
currently conducting experiments to ascertain whether this is the case.
Inhibitory effects could also be caused by the well-described transcriptional controls of cytokine genes and cytokine-activated genes based on positive and negative sequence-specific DNA-binding NFs (reviewed in 45 . Competition for binding different STAT proteins (STAT-binding elements) could explain some of the effects of IL-4 (46). However, the effect would be immediate and could not explain why IL-4 takes 4 h to be fully effective. Clearly, more experiments and much greater knowledge will be needed to determine whether these or other possible explanations are responsible for our observations.
Cytokine effects on M activation are strongly influenced by the
stimulation conditions (cytokine concentration, timing of cytokine
addition), the source of M (bone marrow, peritoneal,
monocyte-derived, alveolar), and the state of activation of the M,
even before species differences are considered. Nevertheless, the
demonstration of distinct and exclusive pathways for M maturation in
vitro by Riches et al. (9) clearly provides a hypothesis to account for
M heterogeneity and a potential explanation for their multiple
postulated roles. This approach has the advantage of examining the
effect of a variety of combinations of cytokines at different doses and
exposure sequences, and we found that the sequence of cytokine exposure
plays a major role in M differentiation. The situation in vivo is
even more complex, because M would be subject to a wide variety of
receptor-mediated events in addition to those that are dependent upon
cytokine receptors. In vivo, M are exposed to chemokines and
interact with adhesion molecules even before they are exposed to the
cytokine environment in the inflamed tissue in which Ig (47) and
complement receptors (48) may be ligated, as well as receptors for
extracellular matrix, including integrins and CD44, and receptors such
as CD40 that bind other cells. Consequently, we are now
conducting studies to examine M differentiation under conditions
that are much closer to the in vivo situation.
Finally, there are a number of implications to our observation that
certain cytokines induce M to develop specific functions while
simultaneously rendering the M temporarily unresponsive to later
stimulation with cytokines with opposing effects. Such a mechanism
might profoundly affect autoregulation by cytokines and may suggest
that the primary effect of the down-regulation of cytokines is to
program the next wave of M to develop a different function.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Lars-Peter Erwig, Department of Medicine and Therapeutics, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, U.K. E-mail address:
3 Abbreviations used in this paper: M, macrophage(s); BMDM, bone marrow-derived macrophage; NO, nitric oxide; IGF-1, insulin-like growth factor-1; PMN, polymorphonuclear leukocyte; SOCS, suppressor of cytokine signaling; JAK, Janus kinase.
Received for publication January 20, 1998. Accepted for publication April 17, 1998.
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References |
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 R. J. Flynn and G. Mulcahy Possible Role for Toll-Like Receptors in Interaction of Fasciola hepatica Excretory/Secretory Products with Bovine Macrophages Infect. Immun., February 1, 2008; 76(2): 678 - 684. [Abstract] [Full Text] [PDF]
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A. D. Joshi, T. Raymond, A. L. Coelho, S. L. Kunkel, and C. M. Hogaboam A systemic granulomatous response to Schistosoma mansoni eggs alters responsiveness of bone marrow-derived macrophages to Toll-like receptor agonists J. Leukoc. Biol., February 1, 2008; 83(2): 314 - 324. [Abstract] [Full Text] [PDF]
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 L.-P. Erwig and P. M. Henson Immunological Consequences of Apoptotic Cell Phagocytosis Am. J. Pathol., July 1, 2007; 171(1): 2 - 8. [Abstract] [Full Text] [PDF]
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Y. de Kozak, B. Omri, J. R. Smith, M.-C. Naud, B. Thillaye-Goldenberg, and P. Crisanti Protein Kinase C{zeta} (PKC{zeta}) Regulates Ocular Inflammation and Apoptosis in Endotoxin-Induced Uveitis (EIU): Signaling Molecules Involved in EIU Resolution by PKC{zeta} Inhibitor and Interleukin-13 Am. J. Pathol., April 1, 2007; 170(4): 1241 - 1257. [Abstract] [Full Text] [PDF]
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 L.-P. Erwig, K. A. McPhilips, M. W. Wynes, A. Ivetic, A. J. Ridley, and P. M. Henson Differential regulation of phagosome maturation in macrophages and dendritic cells mediated by Rho GTPases and ezrin-radixin-moesin (ERM) proteins PNAS, August 22, 2006; 103(34): 12825 - 12830. [Abstract] [Full Text] [PDF]
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 I. O. Gordon and R. S. Freedman Defective Antitumor Function of Monocyte-Derived Macrophages from Epithelial Ovarian Cancer Patients Clin. Cancer Res., March 1, 2006; 12(5): 1515 - 1524. [Abstract] [Full Text] [PDF]
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C. J. Calder, L. B. Nicholson, and A. D. Dick A Selective Role for the TNF p55 Receptor in Autocrine Signaling following IFN-{gamma} Stimulation in Experimental Autoimmune Uveoretinitis J. Immunol., November 15, 2005; 175(10): 6286 - 6293. [Abstract] [Full Text] [PDF]
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H. M. Wilson, S. Chettibi, C. Jobin, D. Walbaum, A. J. Rees, and D. C. Kluth Inhibition of Macrophage Nuclear Factor-{kappa}B Leads to a Dominant Anti-Inflammatory Phenotype that Attenuates Glomerular Inflammation in Vivo Am. J. Pathol., July 1, 2005; 167(1): 27 - 37. [Abstract] [Full Text] [PDF]
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 J. M. Routes, K. Morris, M. C. Ellison, and S. Ryan Macrophages Kill Human Papillomavirus Type 16 E6-Expressing Tumor Cells by Tumor Necrosis Factor Alpha- and Nitric Oxide-Dependent Mechanisms J. Virol., January 1, 2005; 79(1): 116 - 123. [Abstract] [Full Text] [PDF]
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N. Taylor, K. McConnachie, C. Calder, R. Dawson, A. Dick, J. D. Sedgwick, and J. Liversidge Enhanced Tolerance to Autoimmune Uveitis in CD200-Deficient Mice Correlates with a Pronounced Th2 Switch in Response to Antigen Challenge J. Immunol., January 1, 2005; 174(1): 143 - 154. [Abstract] [Full Text] [PDF]
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 R. P. Hobson, C. A. Munro, S. Bates, D. M. MacCallum, J. E. Cutler, S. E. M. Heinsbroek, G. D. Brown, F. C. Odds, and N. A.R. Gow Loss of Cell Wall Mannosylphosphate in Candida albicans Does Not Influence Macrophage Recognition J. Biol. Chem., September 17, 2004; 279(38): 39628 - 39635. [Abstract] [Full Text] [PDF]
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 D O' Gradaigh, D Ireland, S Bord, and J E Compston Joint erosion in rheumatoid arthritis: interactions between tumour necrosis factor {alpha}, interleukin 1, and receptor activator of nuclear factor {kappa}B ligand (RANKL) regulate osteoclasts Ann Rheum Dis, April 1, 2004; 63(4): 354 - 359. [Abstract] [Full Text] [PDF]
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 R. Wu, K. H. Van der Hoek, N. K. Ryan, R. J. Norman, and R. L. Robker Macrophage contributions to ovarian function Hum. Reprod. Update, March 1, 2004; 10(2): 119 - 133. [Abstract] [Full Text] [PDF]
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 D. O'Gradaigh and J. E. Compston T-cell involvement in osteoclast biology: implications for rheumatoid bone erosion Rheumatology, February 1, 2004; 43(2): 122 - 130. [Full Text] [PDF]
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A. W. M. Minto, L.-P. Erwig, and A. J. Rees Heterogeneity of Macrophage Activation in Anti-Thy-1.1 Nephritis Am. J. Pathol., November 1, 2003; 163(5): 2033 - 2041. [Abstract] [Full Text] [PDF]
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 L.-P. Erwig, D. C. Kluth, and A. J. Rees Macrophage heterogeneity in renal inflammation Nephrol. Dial. Transplant., October 1, 2003; 18(10): 1962 - 1965. [Full Text] [PDF]
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A. D. Dick, D. Carter, M. Robertson, C. Broderick, E. Hughes, J. V. Forrester, and J. Liversidge Control of myeloid activity during retinal inflammation J. Leukoc. Biol., August 1, 2003; 74(2): 161 - 166. [Abstract] [Full Text] [PDF]
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M. Robertson, J. Liversidge, J. V. Forrester, and A. D. Dick Neutralizing Tumor Necrosis Factor-{alpha} Activity Suppresses Activation of Infiltrating Macrophages in Experimental Autoimmune Uveoretinitis Invest. Ophthalmol. Vis. Sci., July 1, 2003; 44(7): 3034 - 3041. [Abstract] [Full Text] [PDF]
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D. S. Gregerson and J. Yang CD45-Positive Cells of the Retina and Their Responsiveness to In Vivo and In Vitro Treatment with IFN-{gamma} or Anti-CD40 Invest. Ophthalmol. Vis. Sci., July 1, 2003; 44(7): 3083 - 3093. [Abstract] [Full Text] [PDF]
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 J.-P. Herbeuval, C. Lambert, O. Sabido, M. Cottier, P. Fournel, M. Dy, and C. Genin Macrophages From Cancer Patients: Analysis of TRAIL, TRAIL Receptors, and Colon Tumor Cell Apoptosis J Natl Cancer Inst, April 16, 2003; 95(8): 611 - 621. [Abstract] [Full Text] [PDF]
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T. A. Miura, K. Morris, S. Ryan, J. L. Cook, and J. M. Routes Adenovirus E1A, Not Human Papillomavirus E7, Sensitizes Tumor Cells to Lysis by Macrophages Through Nitric Oxide- and TNF-{alpha}-Dependent Mechanisms Despite Up-Regulation of 70-kDa Heat Shock Protein J. Immunol., April 15, 2003; 170(8): 4119 - 4126. [Abstract] [Full Text] [PDF]
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 Y. Ikezumi, R. C. Atkins, and D. J. Nikolic-Paterson Interferon-{gamma} Augments Acute Macrophage-Mediated Renal Injury Via a Glucocorticoid-Sensitive Mechanism J. Am. Soc. Nephrol., April 1, 2003; 14(4): 888 - 898. [Abstract] [Full Text] [PDF]
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 D A Carter and A D Dick Lipopolysaccharide/interferon-{gamma} and not transforming growth factor {beta} inhibits retinal microglial migration from retinal explant Br J Ophthalmol, April 1, 2003; 87(4): 481 - 487. [Abstract] [Full Text] [PDF]
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C. Broderick, R. M. Hoek, J. V. Forrester, J. Liversidge, J. D. Sedgwick, and A. D. Dick Constitutive Retinal CD200 Expression Regulates Resident Microglia and Activation State of Inflammatory Cells during Experimental Autoimmune Uveoretinitis Am. J. Pathol., November 1, 2002; 161(5): 1669 - 1677. [Abstract] [Full Text] [PDF]
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S. Mitchell, G. Thomas, K. Harvey, D. Cottell, K. Reville, G. Berlasconi, N. A. Petasis, L. Erwig, A. J. Rees, J. Savill, et al. Lipoxins, Aspirin-Triggered Epi-Lipoxins, Lipoxin Stable Analogues, and the Resolution of Inflammation: Stimulation of Macrophage Phagocytosis of Apoptotic Neutrophils In Vivo J. Am. Soc. Nephrol., October 1, 2002; 13(10): 2497 - 2507. [Abstract] [Full Text] [PDF]
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M. J. Robertson, L. P. Erwig, J. Liversidge, J. V. Forrester, A. J. Rees, and A. D. Dick Retinal Microenvironment Controls Resident and Infiltrating Macrophage Function during Uveoretinitis Invest. Ophthalmol. Vis. Sci., July 1, 2002; 43(7): 2250 - 2257. [Abstract] [Full Text] [PDF]
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J. Liversidge, A. Dick, and S. Gordon Nitric Oxide Mediates Apoptosis Through Formation of Peroxynitrite and Fas/Fas-Ligand Interactions in Experimental Autoimmune Uveitis Am. J. Pathol., March 1, 2002; 160(3): 905 - 916. [Abstract] [Full Text] [PDF]
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K. R. B. Bastos, J. M. Alvarez, C. R. F. Marinho, L. V. Rizzo, and M. R. D'Imperio Lima Macrophages from IL-12p40-deficient mice have a bias toward the M2 activation profile J. Leukoc. Biol., February 1, 2002; 71(2): 271 - 278. [Abstract] [Full Text] [PDF]
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M. Hesse, M. Modolell, A. C. La Flamme, M. Schito, J. M. Fuentes, A. W. Cheever, E. J. Pearce, and T. A. Wynn Differential Regulation of Nitric Oxide Synthase-2 and Arginase-1 by Type 1/Type 2 Cytokines In Vivo: Granulomatous Pathology Is Shaped by the Pattern of L-Arginine Metabolism J. Immunol., December 1, 2001; 167(11): 6533 - 6544. [Abstract] [Full Text] [PDF]
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Y. Wang, I. Goldschneider, J. O’Rourke, and R. E. Cone Blood mononuclear cells induce regulatory NK T thymocytes in anterior chamber-associated immune deviation J. Leukoc. Biol., May 1, 2001; 69(5): 741 - 746. [Abstract] [Full Text]
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D. C. Kluth, C. V. Ainslie, W. P. Pearce, S. Finlay, D. Clarke, I. Anegon, and A. J. Rees Macrophages Transfected with Adenovirus to Express IL-4 Reduce Inflammation in Experimental Glomerulonephritis J. Immunol., April 1, 2001; 166(7): 4728 - 4736. [Abstract] [Full Text] [PDF]
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B. Namangala, P. De Baetselier, W. Noël, L. Brys, and A. Beschin Alternative versus classical macrophage activation during experimental African trypanosomosis J. Leukoc. Biol., March 1, 2001; 69(3): 387 - 396. [Abstract] [Full Text]
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A. D. Dick, C. Broderick, J. V. Forrester, and G. J. Wright Distribution of OX2 Antigen and OX2 Receptor within Retina Invest. Ophthalmol. Vis. Sci., January 1, 2001; 42(1): 170 - 176. [Abstract] [Full Text]
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 A. Panoskaltsis-Mortari, D. H. Ingbar, P. Jung, I. Y. Haddad, P. B. Bitterman, O. D. Wangensteen, C. L. Farrell, D. L. Lacey, and B. R. Blazar KGF pretreatment decreases B7 and granzyme B expression and hastens repair in lungs of mice after allogeneic BMT Am J Physiol Lung Cell Mol Physiol, May 1, 2000; 278(5): L988 - L999. [Abstract] [Full Text] [PDF]
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J. S. Duffield, L.-P. Erwig, X.-q. Wei, F. Y. Liew, A. J. Rees, and J. S. Savill Activated Macrophages Direct Apoptosis and Suppress Mitosis of Mesangial Cells J. Immunol., February 15, 2000; 164(4): 2110 - 2119. [Abstract] [Full Text] [PDF]
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L.-P. Erwig, K. Stewart, and A. J. Rees Macrophages from Inflamed but Not Normal Glomeruli Are Unresponsive to Anti-Inflammatory Cytokines Am. J. Pathol., January 1, 2000; 156(1): 295 - 301. [Abstract] [Full Text] [PDF]
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