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Department of Surgery, University of Minnesota, Minneapolis, MN 55455
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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or LPS than
macrophages from Th2 strains (BALB/c, DBA/2). In marked contrast, LPS
stimulates Th2, but not Th1, macrophages to increase arginine
metabolism to ornithine. Thus, M-1/M-2 does not simply describe
activated or unactivated macrophages, but cells expressing distinct
metabolic programs. Because NO inhibits cell division, while ornithine
can stimulate cell division (via polyamines), these results also
indicate that M-1 and M-2 responses can influence inflammatory
reactions in opposite ways. Macrophage TGF-ß1, which inhibits
inducible NO synthase and stimulates arginase, appears to play an
important role in regulating the balance between M-1 and M-2. M-1/M-2
phenotypes are independent of T or B lymphocytes because C57BL/6 and
BALB/c NUDE or SCID macrophages also exhibit M-1/M-2. Indeed, M-1/M-2
proclivities are magnified in NUDE and SCID mice. Finally, C57BL/6 SCID
macrophages cause CB6F1 lymphocytes to increase
IFN- production, while BALB/c SCID macrophages increase TGF-ß
production. Together, the results indicate that M-1- or M-2-dominant
macrophage responses can influence whether Th1/Th2 or other types of
inflammatory responses occur. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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, which causes
macrophage activation, are called Th1. Th2 immune responses are
associated with IL-4, IL-5, and IL-10, which, in contrast to IFN-,
inhibit macrophage activation and instead stimulate Ab production.
Leishmania major is the prototypical model of Th1 and Th2
responses. Resistant C57BL/6 T lymphocytes produce IFN- that
activates macrophages to produce NO and kill the parasite, while
susceptible BALB/c T lymphocytes instead produce more IL-4 that
suppresses macrophages (13, 14). In addition, IL-4 and
other Th2 cytokines have been reported to increase macrophage arginine
metabolism via argininase, which produces ornithine and urea
(15). T lymphocytes of other strains of mice have also
been reported to have a tendency to produce Th1 (B10D2) or Th2 (DBA/2)
cytokine profiles (16). Whereas the aforementioned results clearly indicate that T lymphocytes from different strains of mice have a tendency to produce cytokines that activate or inhibit macrophages, other reports have shown that macrophages from the Th1 strains are more easily activated than those from Th2 strains (17, 18, 19, 20, 21). Thus, the ability to generate a Th1- or Th2-type response does not wholly depend on T lymphocytes. That macrophages themselves may determine immunologic outcomes is suggested by results such as those showing that Leishmania infection of macrophages can increase their ability to stimulate a Th2 response instead of a Th1 response (22). In a related vein, it has been reported recently that dendritic cells have the potential to shepherd T lymphocytes into Th1- or Th2-dominant phenotypes (23, 24, 25, 26). That macrophage and dendritic cells can both influence lymphocyte responses is in keeping with the knowledge that macrophages are a precursor of dendritic cells (27).
In the course of our ongoing investigations into factors that regulate macrophage arginine metabolism, we found evidence that Th1 and Th2 macrophages not only differ in their ability to be activated in the classical sense, but made qualitatively different responses to the same stimuli. For example, we confirmed that macrophages from Th1-like strains are more easily activated to produce NO than macrophages from Th2-like strains. More importantly, however, we also discovered that in response to certain stimuli (LPS), Th2 macrophages not only do not produce NO, but instead increase arginine metabolism to ornithine; Th1 macrophages do not. Because NO inhibits cell replication (7, 28, 29), while ornithine (as a precursor of polyamines) can stimulate replication, these results suggested that macrophages from Th1 and Th2 mice can influence immune reactions in opposite ways. The results to follow provide evidence to support this postulate and will show that macrophages from Th1 and Th2 strains differentially influence whether Th1, Th2, or other immune response occurs. We propose that these different macrophage responses be termed M-1 and M-2.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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C57BL/6, B10D2, DBA/2, BALB/c, B6D2F1, CB6F1, C57BL/6J- Hfh11nu, BALB/cByJ-Hfh11nu, C57BL/6J-Prkdcscid/SzJ, and BALB/cByJ-Prkdcscid/J female mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice used for experiments were between 9 and 14 wk old. They were routinely tested for common murine pathogens by the University of Minnesota Research Animal Resources (Minneapolis, MN). Mice were euthanized with carbon dioxide.
Spleen cell culture
Spleens from five mice were pooled and cultured for 3 days in
the presence of 5 µg/ml Con A, as previously described
(30). The medium employed is described below. Supernatants
were collected and assayed for IFN- and IL-4.
Resident peritoneal macrophage culture
Resident peritoneal macrophages
(PEC)3 were cultured
as in preceding studies (30, 31). Briefly, PEC from five
or more mice were harvested by three injections of 5 ml PBS containing
antibiotics. PEC were resuspended in RPMI 1640 supplemented with
antibiotics, 1 x
10-2 M morpholinopropane
sulfonic acid (buffer), 5 x
10-5 M 2-ME, BSA (2.5
mg/ml), transferrin (10 µg/ml), and insulin (1 µU/ml). Tissue
culture reagents were purchased from Life Technologies (Gaithersburg,
MD) or Sigma (St. Louis, MO). All experiments were performed in this
serum-free medium (SFM), except for the spleen cell culture in Fig. 1
.
In this experiment, the basal medium was supplemented with 10% FBS
(HyClone, Logan, UT), as in preceding studies (30). All
medium components contained less than 0.015 ng endotoxin/ml. Cells were
plated at 3 x 106 or 1 x
106/ml in 0.1 ml in quadruplicate flat-bottom
microtiter wells. Adherent and nonadherent cells were separated by
repeated washing after a 2-h incubation at 37°C in an atmosphere of
7% CO2. PEC were then cultured for 48 h
before supernatant collection to measure NO, cytokine production, or
amino acid metabolism. IFN- was purchased from Life Technologies.
LPS 055:B5 was purchased from Difco (Detroit, MI). Unless indicated,
macrophages were cultured with 500 pg/ml IFN- (10 U/ml) and/or 1
ng/ml LPS. Any experiment comparing strains of mice was head to head,
in that it was conducted on the same day with the same medium,
reagents, etc.
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NO production by PEC was measured in supernatants collected after 48 h of culture, as described previously (32). Briefly, 0.05 ml of Griess reagent (prepared with reagents from Sigma) was added to 0.05 ml of supernatant, and absorbance was read at 550 nm using an automated plate reader. Nitrite concentration was calculated from a NaNO2 standard curve.
IFN-, IL-4, and TGF-ß1 determination
Cytokines in cell culture supernatants were measured using
commercially available kits from Genzyme (Cambridge, MA) (Figs. 1
and 3) or R&D Systems (Minneapolis, MN) (Fig. 6). The two companies’ kits
behaved similarly. We switched companies by necessity; R&D Systems
purchased Genzyme’s ELISA kit division. The sensitivity limits for the
assays were 5 pg/ml (IFN- and IL-4) and 7 pg/ml (TGF-ß1). Latent
plus active TGF-ß was measured. Experimental values were determined
from standard curves calculated in Excel. The SFM employed contained
undetectable quantities of these cytokines.
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Amino acids were measured as in previous publications (31). Briefly, samples for amino acid analysis were deproteinized with a solution containing sulfosalicylic (Seraprep; Pickering Labs, Mountain View, CA) and 250 µM norleucine internal standard. Denatured protein is removed by centrifugation at 14,000 x g for 5 min. The pH of the supernatant was adjusted to 2.2 by the addition of a lithium-based buffer solution. Amino acids were measured using a Dionex BioLC Amino Acid Analyzer System (Dionex, Sunnyvale, CA) with lithium eluents. Samples with amino acid concentrations greater then 5 µM can be measured with this procedure. Variation between replicate amino acid runs routinely averaged less than 5%.
Anti-TGF-ß1 Ab
Polyclonal neutralizing Ab against TGF-ß1 (catalog AB-101-NA) and control chicken Ig were purchased from R&D Systems and were used at a concentration of 50 µg/ml.
Macrophage phagocytosis
After 48 h of culture, 0.05 ml of Fluoresbrite Plain YG 2
µm microspheres (Polysciences, Warrington, PA) at a concentration of
3 x 108 beads/ml were added per well (
50
beads/cell). A test plate (37°C) and a control plate (4°C) were
incubated for 2 h. At that time, the wells were washed three times
each with 0.2 ml of PBS to remove beads not actively phagocytosed. A
final 0.1 ml of PBS was added and the plate was read at 480 nm on a
Perkin-Elmer Luminescence Spectrometer (Perkin-Elmer, Beaconsfield,
Buckinghamshire, U.K.). Fluorescence in replicate control wells was
subtracted from the test wells to calculate the phagocytic index.
Macrophage/lymphocyte coculture
PEC from C57BL/6 or BALB/c SCID mice were collected, irradiated (1000 rad), and then cultured at 1 x 105/well in 0.2 ml. After 2 days, 0.1 ml was removed and 3 x 105 (C57BL/6 x BALB/c)F1 spleen cells depleted of macrophages by adherence were added in 0.05 ml to the macrophage cultures. Con A (0.06 µg/ml) was added in 0.05 ml. After 2 days, 1 µCi [3H]thymidine (6.7 Ci/mmol) was added in 0.025 ml. Cells were harvested 16 h later, and [3H]thymidine uptake was determined.
Data presentation
Data reported are means ± 1 SD from a representative
experiment. The error bars represent the average ± SD of
quadruplicate microtiter wells. If the SD was smaller than the width of
the bar, it is not shown. All of the experiments reported in this work
were repeated two to three times with the same pattern of results.
Student’s unpaired t test was used to analyze statistical
significance. Inverse correlation statistics (Pearson’s correlation
coefficient (
) and p value) were obtained from a simple
regression analysis (exponential model) using GB-Stat PPC 5.5.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Before undertaking a detailed comparison of macrophages from
selected Th1- and Th2-type mouse strains, it was considered important
to first characterize their lymphocyte cytokine propensities. It can be
seen first in Fig. 1 that Con A
stimulation of spleen cells from C57BL/6 mice results in a Th1 response
characterized by high IFN-/low IL-4 production, while BALB/c spleen
cells exhibit a Th2 response with low IFN-/high IL-4 production.
B10D2 spleen cells also exhibit the Th1 profile of high IFN-/low
IL-4 production. DBA/2 spleen cells exhibit something of an
intermediate phenotype, producing a significant quantity of both
IFN- and IL-4. B10D2 and DBA/2 were chosen for analysis because they
share major histocompatibility type H-2d with
BALB/c mice and they are two other strains that have been reported to
exhibit Th1 and Th2 T lymphocyte tendencies, respectively
(16). Because the polyclonal activator Con A was used as
the stimulant, the results also demonstrate that the tendencies of mice
to produce IFN- or IL-4 are Ag independent. These results provide a
background for the macrophage studies by defining the T lymphocyte
cytokine profiles of the strains of mice to be used.
Differential arginine metabolism by Th1 and Th2 macrophages
Results such as those in Fig. 1 suggest that lymphocytes from
certain inbred mice have a predilection to produce IFN- and/or IL-4.
However, if differences in cytokines produced by lymphocytes could
wholly explain susceptibility to diseases like Leishmania
major, then macrophages from C57BL/6 and BALB/c should be
similarly responsive to IFN-, the primary Th1 cytokine that
activates macrophages. Fig. 2 shows that
this is not the case. It can be seen, in agreement with some recent
reports (17, 18, 19, 20, 21), that PEC from two Th1-like strains
(C57BL/6 and B10D2) are more easily activated by IFN- to produce NO
than macrophages from the two Th2-like strains (BALB/c, DBA/2). The
concentration of citrulline, the other product of the iNOS pathway,
parallels that of NO, as would be expected. It can also be seen that
C57BL/6 and B10D2 macrophages respond more readily to LPS than DBA/2 or
BALB/c macrophages, in agreement with a recent report
(21). The simplest explanation for these data is that Th1
macrophages become activated and Th2 do not.
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Thus, the pathway macrophages utilize to metabolize arginine could
alter the outcome of inflammation in opposite ways. Therefore, it was
also of interest to compare not only the iNOS, but also the arginase
pathway in Th1/Th2 macrophages. Results in Fig. 2 show that macrophages
from Th1 and Th2 mice can activate opposing pathways of arginine
metabolism in response to the same stimuli. Specifically, the results
in Fig. 2 demonstrate that in this experiment, Th2 macrophages not only
do not produce NO in response to LPS, but instead increase their
production of ornithine/urea. Specifically, there is a 91% increase
for DBA/2 and a 103% increase for BALB/c in the extracellular
ornithine concentration. In contrast, Th1 macrophages, if anything,
slightly decreased ornithine production in response to LPS. Thus, these
results directly demonstrate that under the same circumstances, Th1 and
Th2 macrophages can be activated to express qualitatively different
metabolic programs, which could affect inflammatory outcomes in
opposite ways. In vivo evidence of such differential changes in
macrophage arginine metabolism includes the findings that macrophages
up-regulate NO production during tumor rejection, and up-regulate
ornithine production during progressive tumor growth (41).
From the results in this section, we propose that macrophages
predominately expressing the iNOS or arginase pathway be termed M-1 or
M-2, respectively.
Another difference observed between the way that M-1 or M-2 macrophages
respond is that LPS strongly synergizes with IFN- in DBA/2 and
BALB/c macrophages, but much less so with C57BL/6 or B10D2. How can
these results be explained in terms of the two-signal concept of
macrophage activation (42, 43)? Part of the explanation
seems to be that some of the original experiments were performed with
BALB/c mice, in which strong synergy between IFN- and LPS is
observed. Also, most investigators use medium supplemented with 10%
FBS, whereas the experiments reported in this work and in certain other
recent reports (44) have used SFM. SFM was selected
because results to follow will show that 10% FBS contains enough
TGF-ß to inhibit macrophage activation. In turn, it may only be
necessary to use both IFN- and LPS to optimally stimulate
macrophages if there is a significant quantity of TGF-ß in the
medium.
Macrophage TGF-ß1 production is inversely proportional to macrophage NO production in M-1 and M-2 strains of mice
Results in the preceding section indicate that macrophages from M-1 and M-2 strains have a propensity to activate the iNOS or arginase pathway, respectively. To probe the molecular basis for these differences, TGF-ß1 production by M-1 and M-2 macrophages was measured. TGF-ß1 was selected for study because it is known to be a powerful inhibitor of macrophage NO production (45, 46). In addition, TGF-ß1 has been reported to increase arginase activity (47). In vivo, the level of TGF-ß correlates with susceptibility to Leishmania (20, 48, 49). Also, inhibition of TGF-ß1 has been shown to heighten resistance to diseases, in which macrophages are the likely effector (50). On the other hand, NO has been reported to inhibit macrophage TGF-ß production (44). Thus, although the foregoing results indicate that a chicken or egg question remains regarding who regulates whom, important links exist between TGF-ß and NO. In turn, it was considered important to determine whether there is a relationship between NO and TGF-ß production in M-1 and M-2 macrophages.
It can be seen first in Fig. 3 that
C57BL/6 and B10D2 macrophage again responded more readily to IFN- by
production of NO. It can be seen that BALB/c macrophages in this
experiment produced NO in response to LPS. We do observe some day to
day variation in responsiveness to LPS, but not IFN-. The
variability occurs despite using medium components from the same lot
and with very low endotoxin, and using mice of the same age, etc. On
average, however, BALB/c and DBA macrophages both produce significantly
less NO than C57BL/6 or B10D2 in response to either IFN- or LPS in
agreement with the results of others (17, 18, 19, 20, 21). Most
importantly, BALB/c macrophages again responded in a qualitatively
different manner to LPS than C57BL/6, as evidenced by increased
ornithine production. Specifically, medium ornithine concentrations
(µM) in the experiment in Fig. 3 were: BALB/c, NONE = 564; 500
IFN- = 659; LPS = 761; IFN- + LPS = 394. C57BL/6,
NONE = 320; 500 IFN- = 239; LPS = 236; IFN- +
LPS = 165.
As for the production of TGF-ß by M-1 and M-2 macrophages, it can be
seen that both produce a significant quantity of TGF-ß1 (200–400
pg/ml); no consistent difference between strains has been observed.
However, more importantly, it can be seen that the quantity of NO
produced by M-1 and M-2 macrophages stimulated with different
concentrations of IFN- or LPS is inversely proportional to the
quantity of TGF-ß1 produced. That there is a causal link between NO
and TGF-ß1 production is suggested by the findings that in all four
strains of mice examined, and with essentially all of the different
stimuli, a highly significant inverse relationship is observed
( = -0.81; p < 0.0001). That macrophage
TGF-ß is physiologically important is suggested by the fact that the
quantity of TGF-ß1 produced (400 pg/ml) is in the range that has been
shown to inhibit NO production (45). Although total
(latent plus active) TGF-ß1 was measured in this study, macrophages
are known to activate latent TGF-ß1, so the values are in the correct
range (51). Together, these results are consistent with
the conclusion that M-1- and M-2-dominant responses occur, in part,
because of autocrine macrophage regulation by TGF-ß1.
Macrophage TGF-ß1 is an endogenous inhibitor of NO production
The results in Fig. 3 suggested that TGF-ß1 produced by
macrophages plays a role in down-regulating NO production, or vice
versa. To measure TGF-ß1, it was necessary to use SFM because 10%
FBS that is used by most investigators provides about 750 pg/ml
TGF-ß1, and thus would obscure that produced by macrophages. Evidence
that the quantity of TGF-ß1 contained in medium supplemented with
10% FBS is sufficient to inhibit macrophage NO production is shown in
Fig. 4A. Macrophages cultured
in a medium containing 10% FBS produce less NO than macrophages
cultured in SFM only supplemented with BSA, transferrin, and insulin.
Also, addition of FBS to SFM inhibits NO production, indicating that
inhibitory components of FBS rather than stimulatory components in SFM
are responsible. That the inhibitory component in FBS is TGF-ß1 is
further suggested by the finding that the addition of 750 pg/ml
TGF-ß1 to SFM (the same concentration provided by 10% FBS) inhibits
NO production. Thus, the use of SFM, in addition to allowing TGF-ß1
to be measured, also serves to demonstrate that culturing macrophages
in standard FBS-containing medium may be misleading because the
TGF-ß1 artificially inhibits macrophage activation.
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B that IFN-
stimulates significant NO production. However, more importantly,
addition of anti-TGF-ß1 Ab without IFN- also increases NO
production. That endogenously produced TGF-ß1 inhibits macrophage
activation is further evidenced by the additional finding that addition
of IFN- and anti-TGF-ß1 results in the highest level of NO
production. Control Ab (nonimmune chicken Ig) does not stimulate NO
production. Also, anti-TGF-ß1 increases NO production in C3H/He
macrophages, indicating that endotoxin is not responsible for the
activity observed (not shown). Thus, the results in this section
indicate that macrophages produce a quantity of TGF-ß1 that is
sufficient to endogenously down-regulate their activation state.
The impact of TGF-ß1 on macrophages is not subtle. Fig. 4, C, D, and E, shows what PEC look like
after 2 days of culture in SFM alone (C), SFM plus IFN-
(D), or SFM plus IFN- and TGF-ß1 (E). It can
be seen that TGF-ß1 (1 ng/ml) induces a dramatic change in macrophage
morphology, causing them to take on a fibroblast-like appearance. In
addition to their reduced NO production, these TGF-ß-induced long
slender cells have markedly reduced phagocytic capacity. Specifically,
macrophages cultured alone or with IFN- had a phagocytic index of
3.5 ± 0.4 and 5.5 ± 0.5, respectively, while macrophages
cultured in IFN- plus TGF-ß had an index of only 1.5 ± 0.5
(p = 0.0034 and p < 0.0001,
respectively). In this regard, it has been previously reported that
TGF-ß did not decrease phagocytic activity (52). The
most likely explanation for this discrepancy is that we have observed
that 10% FBS (containing TGF-ß) as used in other studies itself
causes macrophages to assume this fibroblast-like appearance. In turn,
addition of exogenous TGF-ß may not have further decreased
phagocytosis under these conditions. It is not clear at present what
functions these fibroblast-like cells induced by TGF-ß do perform.
One possibility being explored is that they exhibit an enhanced Ag
presentation capability because TGF-ß has been shown to promote the
formation of dendritic cells (53).
As for the molecular basis of how TGF-ß1 so dramatically alters macrophage morphology, there are suggestions that its effect may result from changes in arginine metabolism. For example, in a previous publication, we observed that macrophages cultured in a low arginine environment also exhibited this fibroblast-like morphology (54). Also, there have been repeated suggestions that macrophages in culture eventually transform into fibroblasts (55, 56): circumstances again in which the arginine concentration in the medium would have been greatly reduced by the macrophages. Relatedly, TGF-ß1 not only down-regulates the iNOS pathway, but also up-regulates the arginase pathway (47, 57). Thus, perhaps the stimulus for the change in macrophage morphology is low NO concentration, either because of a decrease by TGF-ß or a low extracellular arginine concentration.
Macrophages from C57BL/6 and BALB/c NUDE or SCID mice display exaggerated M-1 or M-2 phenotypes
Results in the preceding sections indicated that macrophages from
Th1 or Th2 mice can respond very differently when confronted with the
same stimuli. Although these results suggest that the macrophages
themselves are different, other explanations were possible. For
example, macrophages could have been bathed in a Th1 or Th2 atmosphere
before culture. Also, a significant number of T lymphocytes could have
been present in the macrophage-enriched cultures. To rule out these
potentialities, we compared NUDE or SCID macrophages with a C57BL/6 or
BALB/c background. It can be seen first in Fig. 5 that macrophages from C57BL/6 NUDE mice
spontaneously produce significant quantities of NO. Addition of
IFN-, LPS, or both does not further increase NO production. C57BL/6
SCID macrophages spontaneously produce even more NO, and again, stimuli
do not further elevate production. Thus, absence of T/B lymphocytes
strongly enhances the M-1 phenotype. Theoretically, NK cells could be
involved here. However, if they are, the results still indicate that
differences between M-1 and M-2 macrophages are not dependent on
Th1/Th2 influence. It can also be seen in Fig. 5 that in contrast to
the up-regulation of the iNOS pathway in C57BL/6 mice, the arginase
pathway is preferentially expressed in BALB/c NUDE and SCID
macrophages. For example, BALB/c NUDE and SCID macrophages produce
about twice the ornithine as age-matched C57BL/6 NUDE macrophages
measured on the same day. BALB/c SCID macrophages did produce NO in
response to IFN-, and produced about the same maximum quantity of NO
as C57BL/6 SCID macrophages. Although an explanation for these results
requires more investigation, one might speculate that an additional
NO-inhibiting cytokine is lost in SCID as compared with NUDE BALB/c
mice. Together, the results in this section suggest that the
qualitative differences in C57BL/6 and BALB/c macrophage arginine
metabolism are not dependent on T or B lymphocytes. Indeed, M-1 and M-2
phenotypes seem exaggerated in their absence, indicating that T and B
lymphocytes play a modulating role.
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Evidence in this communication indicates that macrophages from
Th1- and Th2-type mice can respond in qualitatively different ways to
stimuli, and therefore could differentially influence what type of
lymphocyte responses occur. To test this hypothesis, we again took
advantage of SCID mice with an M-1 (C57BL/6) or M-2 (BALB/c)
background. Macrophages (1 x 105) from
C57BL/6 or BALB/c SCID mice were cultured alone or in the presence of
IFN- or LPS or both for 2 days. The macrophages were irradiated
(1000 rad) before culture to prevent any contribution to proliferation.
Macrophage-depleted spleen cells (3 x 105)
from (C57BL/6 x BALB/c)F1 mice
(CB6F1) were then added, and the
macrophage/lymphocyte cocultures were stimulated with Con A.
F1 lymphocytes were employed so they would not
respond to parental Ags. After 2 days, supernatants were removed for
cytokine analyses and the cultures were pulsed with
[3H]thymidine to measure cell proliferation. It
can be seen first in Fig. 6A
that Con A-induced proliferation of CB6F1
lymphocytes is inhibited to a greater degree by unstimulated C57BL/6
SCID than BALB/c SCID macrophages (p = 0.03).
Specifically, there is a 59% decrease in proliferation upon coculture
with unstimulated C57BL/6 SCID macrophages, whereas proliferation with
unstimulated BALB/c SCID macrophages is the same as with
CB6F1 lymphocytes cultured without exogenous
macrophages. These results are consistent with the findings in Fig. 5
showing that unstimulated C57BL/6 NUDE or SCID macrophages endogenously
produce NO, and therefore would be expected to express more suppressor
macrophage activity (30) than BALB/c SCID macrophages. It
can also be seen in Fig. 6A that proliferation is strongly
inhibited by either C57BL/6 or BALB/c SCID macrophages if they have
been pretreated with IFN- and LPS. These findings are also in
keeping with results in Fig. 5, which showed that BALB/c macrophages
can produce as much NO as C57BL/6 macrophages when stimulated with both
IFN- and LPS.
In addition to affecting lymphocyte proliferation to different degrees,
C57BL/6 and BALB/c SCID macrophages also influence whether Th1- or
Th2-associated cytokines are produced by lymphocytes. Specifically, it
can be seen in Fig. 6B that C57BL/6 SCID macrophages
precultured with IFN- and LPS cause a marked increase in IFN-
production by CB6F1 lymphocytes. BALB/c SCID
macrophages caused no increase. The vast majority of the IFN-
measured in the supernatants was produced by
CB6F1 lymphocytes (T or NK) because only 500
pg/ml IFN- was added to precultured macrophages, and about 6000
pg/ml was produced in the secondary cultures. As for a molecular
explanation for the IFN--inducing ability of C57BL/6 SCID
macrophages, it has been reported that C57BL/6 macrophages produce more
IL-12 than BALB/c macrophages (58). We have also observed
that C57BL/6 macrophages produce more IFN--inducing IL-12 than
BALB/c macrophages (C. D. Mills, unpublished).
In contrast to IFN-, BALB/c SCID macrophages, whether cultured alone
or with IFN- and LPS, caused CB6F1 lymphocytes
to increase production of TGF-ß1 more than C57BL/6 SCID macrophages
(Fig. 6C). Although not strictly a Th2 cytokine, TGF-ß
does favor the production of Th2 responses by inhibiting Th1-induced
macrophage activation. The majority of the TGF-ß produced in the
cocultures seems to be from CB6F1 lymphocytes
(the amount produced in macrophage cultures without lymphocytes is
shown under the histobars).
The quantity of the Th2 cytokine IL-4 produced by
CB6F1 lymphocytes, whether cocultured with
C57BL/6 or BALB/c SCID macrophages, was barely detectable (C57BL/6,
25–30 pg/ml; BALB/c, 10–20 pg/ml). This is much less IL-4 than is
even produced by the low IL-4 parent, C57BL/6, as shown in Fig. 1. In
this regard, offspring of M-1 and M-2 mice ((C57BL/6 x
BALB/c)F1 or C57BL/6 x DBA/2)F1) have
intermediate phenotypes (not shown). Therefore, the reason for low IL-4
does not appear to be the mouse strain employed, but rather that the
serum-free culture conditions do not support IL-4 production like
cultures containing 10% FBS, as in Fig. 1. In summary, the results in
this section demonstrate that M-1 or M-2 macrophages when confronted
with the same stimuli: 1) can affect subsequent lymphocyte
proliferation in different ways; 2) influence whether Th1- or
Th2-dominant cytokines are produced.
The results in this communication provide evidence that macrophages
play a more important role in orchestrating immune responses than is
currently appreciated. If one views immune responses in temporal terms,
however, it is not really surprising that macrophages play a pivotal
role in determining immunological outcomes because they are typically
the first cells to receive danger signals (59). Also, T
lymphocytes require signals normally provided by macrophages or
dendritic cells to respond to Ags (27, 33, 34, 60). In
this regard, although the results in this communication are described
in terms of M-1 or M-2 macrophage responses, dendritic cells are also
likely to be involved in these responses because macrophages are a
precursor for dendritic cells (27). Evidence to support
this postulate includes results discussed earlier that dendritic cells
can stimulate Th1 or Th2 cytokine profiles in vivo (26).
Perhaps M-1- or M-2-dominant responses evolve into dendritic cell
responses that stimulate Th1 or Th2 responses, respectively. At the
same time, because M-1 equates with the production of destructive
molecules such as NO, overexpression of this pathway could inhibit
lymphocyte responses through a suppressor macrophage effect (30, 61, 62, 63), as suggested in Fig. 6.
Our proposed classification of macrophage propensities into M-1 and M-2, while useful for conceptualizing immune responses, certainly could be an oversimplification. In particular, it cannot be concluded from the present results that M-1 or M-2 are clonally separable cells like Th1 and Th2 clones (13). Instead, there may be a continuum of phenotypes between M-1 and M-2 macrophages. Regardless, the functionally important point is that the net macrophage responses to stimuli between common strains of mice vary in fundamentally different ways, and can be independent of T lymphocyte influence. In turn, the results suggest that macrophages can be an important factor in determining whether Th1/Th2 or other immune responses occur. At the same time, although the present results provide evidence that macrophages can influence lymphocyte responses, there are well-established differences in lymphocyte cytokine profiles. Therefore, the type or intensity of immune response that occurs is likely to be a composite of the propensities of macrophages and lymphocytes acting in concert. As an example, our results show that M-2 macrophages have a propensity to express arginase/ornithine production. Other recent results have shown that the Th2 cytokine IL-4 also increases macrophage arginase/ornithine production (64). Therefore, if macrophages from an individual have an M-2 propensity and his T lymphocytes have a Th2 propensity, then one would predict that there would be synergy in stimulating the arginase/ornithine pathway. Conversely, one could also envision circumstances in which macrophages and lymphocytes have opposite propensities, and thus would antagonize each other. Increasing our understanding of the interplay between macrophages, dendritic cells, and lymphocytes should augment our ability to alter the course of immune responses/inflammation as needed.
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2 Address correspondence and reprint requests to Dr. Charles D. Mills, Department of Surgery, University of Minnesota Hospital and Clinic, Box 120, 420 Delaware St. S.E., Minneapolis, MN 55455.
3 Abbreviations used in this paper: PEC, resident peritoneal macrophages; iNOS, inducible NO synthase; SFM, serum-free medium.
Received for publication January 3, 2000. Accepted for publication March 30, 2000.
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L. C. Gavrilescu, B. A. Butcher, L. Del Rio, G. A. Taylor, and E. Y. Denkers STAT1 Is Essential for Antimicrobial Effector Function but Dispensable for Gamma Interferon Production during Toxoplasma gondii Infection Infect. Immun., March 1, 2004; 72(3): 1257 - 1264. [Abstract] [Full Text] [PDF]
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T. H. Wu, C. N. Pabin, Z. Qin, T. Blankenstein, M. Philip, J. Dignam, K. Schreiber, and H. Schreiber Long-Term Suppression of Tumor Growth by TNF Requires a Stat1- and IFN Regulatory Factor 1-Dependent IFN-{gamma} Pathway but Not IL-12 or IL-18 J. Immunol., March 1, 2004; 172(5): 3243 - 3251. [Abstract] [Full Text] [PDF]
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 J. Yamada, K. Maruyama, Y. Sano, S. Kinoshita, Y. Murata, and J. Hamuro Promotion of Corneal Allograft Survival by the Induction of Oxidative Macrophages Invest. Ophthalmol. Vis. Sci., February 1, 2004; 45(2): 448 - 454. [Abstract] [Full Text] [PDF]
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T. Katakura, M. Miyazaki, M. Kobayashi, D. N. Herndon, and F. Suzuki CCL17 and IL-10 as Effectors That Enable Alternatively Activated Macrophages to Inhibit the Generation of Classically Activated Macrophages J. Immunol., February 1, 2004; 172(3): 1407 - 1413. [Abstract] [Full Text] [PDF]
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D. H. Dockrell, H. M. Marriott, L. R. Prince, V. C. Ridger, P. G. Ince, P. G. Hellewell, and M. K. B. Whyte Alveolar Macrophage Apoptosis Contributes to Pneumococcal Clearance in a Resolving Model of Pulmonary Infection J. Immunol., November 15, 2003; 171(10): 5380 - 5388. [Abstract] [Full Text] [PDF]
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H. Wang, K. A. Hosiawa, W. Min, J. Yang, X. Zhang, B. Garcia, T. E. Ichim, D. Zhou, D. Lian, D. J. Kelvin, et al. Cytokines Regulate the Pattern of Rejection and Susceptibility to Cyclosporine Therapy in Different Mouse Recipient Strains After Cardiac Allografting J. Immunol., October 1, 2003; 171(7): 3823 - 3836. [Abstract] [Full Text] [PDF]
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A. C. La Flamme, K. Ruddenklau, and B. T. Backstrom Schistosomiasis Decreases Central Nervous System Inflammation and Alters the Progression of Experimental Autoimmune Encephalomyelitis Infect. Immun., September 1, 2003; 71(9): 4996 - 5004. [Abstract] [Full Text] [PDF]
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Y. Liu, J. A. Van Ginderachter, L. Brys, P. De Baetselier, G. Raes, and A. B. Geldhof Nitric Oxide-Independent CTL Suppression during Tumor Progression: Association with Arginase-Producing (M2) Myeloid Cells J. Immunol., May 15, 2003; 170(10): 5064 - 5074. [Abstract] [Full Text] [PDF]
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S. A. McClellan, X. Huang, R. P. Barrett, N. van Rooijen, and L. D. Hazlett Macrophages Restrict Pseudomonas aeruginosa Growth, Regulate Polymorphonuclear Neutrophil Influx, and Balance Pro- and Anti-Inflammatory Cytokines in BALB/c Mice J. Immunol., May 15, 2003; 170(10): 5219 - 5227. [Abstract] [Full Text] [PDF]
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D. M. Mosser The many faces of macrophage activation J. Leukoc. Biol., February 1, 2003; 73(2): 209 - 212. [Full Text] [PDF]
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 F L M Ricciardolo Multiple roles of nitric oxide in the airways Thorax, February 1, 2003; 58(2): 175 - 182. [Abstract] [Full Text] [PDF]
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E. Kuroda and U. Yamashita Mechanisms of Enhanced Macrophage-Mediated Prostaglandin E2 Production and Its Suppressive Role in Th1 Activation in Th2-Dominant BALB/c Mice J. Immunol., January 15, 2003; 170(2): 757 - 764. [Abstract] [Full Text] [PDF]
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V. Bronte, P. Serafini, C. De Santo, I. Marigo, V. Tosello, A. Mazzoni, D. M. Segal, C. Staib, M. Lowel, G. Sutter, et al. IL-4-Induced Arginase 1 Suppresses Alloreactive T Cells in Tumor-Bearing Mice J. Immunol., January 1, 2003; 170(1): 270 - 278. [Abstract] [Full Text] [PDF]
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A. B. Geldhof, J. A. Van Ginderachter, Y. Liu, W. Noel, G. Raes, and P. De Baetselier Antagonistic effect of NK cells on alternatively activated monocytes: a contribution of NK cells to CTL generation Blood, December 1, 2002; 100(12): 4049 - 4058. [Abstract] [Full Text] [PDF]
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W. Noel, G. Hassanzadeh, G. Raes, B. Namangala, I. Daems, L. Brys, F. Brombacher, P. D. Baetselier, and A. Beschin Infection Stage-Dependent Modulation of Macrophage Activation in Trypanosoma congolense-Resistant and -Susceptible Mice Infect. Immun., November 1, 2002; 70(11): 6180 - 6187. [Abstract] [Full Text] [PDF]
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J. S. Welch, L. Escoubet-Lozach, D. B. Sykes, K. Liddiard, D. R. Greaves, and C. K. Glass TH2 Cytokines and Allergic Challenge Induce Ym1 Expression in Macrophages by a STAT6-dependent Mechanism J. Biol. Chem., November 1, 2002; 277(45): 42821 - 42829. [Abstract] [Full Text] [PDF]
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D. A. Hume, I. L. Ross, S. R. Himes, R. T. Sasmono, C. A. Wells, and T. Ravasi The mononuclear phagocyte system revisited J. Leukoc. Biol., October 1, 2002; 72(4): 621 - 627. [Abstract] [Full Text] [PDF]
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E. M. Janssen, M. H. M. Wauben, F. P. Nijkamp, W. van Eden, and A. J. M. van Oosterhout Immunomodulatory Effects of Antigen-Pulsed Macrophages in a Murine Model of Allergic Asthma Am. J. Respir. Cell Mol. Biol., August 1, 2002; 27(2): 257 - 264. [Abstract] [Full Text] [PDF]
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E. Kuroda, T. Kito, and U. Yamashita Reduced Expression of STAT4 and IFN-{gamma} in Macrophages from BALB/c Mice J. Immunol., June 1, 2002; 168(11): 5477 - 5482. [Abstract] [Full Text] [PDF]
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E. Careau, J. Sirois, and E. Y. Bissonnette Characterization of Lung Hyperresponsiveness, Inflammation, and Alveolar Macrophage Mediator Production in Allergy Resistant and Susceptible Rats Am. J. Respir. Cell Mol. Biol., May 1, 2002; 26(5): 579 - 586. [Abstract] [Full Text] [PDF]
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L. Tuckova, J. Novotna, P. Novak, Z. Flegelova, T. Kveton, L. Jelinkova, Z. Zidek, P. Man, and H. Tlaskalova-Hogenova Activation of macrophages by gliadin fragments: isolation and characterization of active peptide J. Leukoc. Biol., April 1, 2002; 71(4): 625 - 631. [Abstract] [Full Text] [PDF]
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J. Huang, F. J. DeGraves, S. D. Lenz, D. Gao, P. Feng, D. Li, T. Schlapp, and B. Kaltenboeck The quantity of nitric oxide released by macrophages regulates Chlamydia-induced disease PNAS, March 19, 2002; 99(6): 3914 - 3919. [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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T. Ravasi, C. Wells, A. Forest, D. M. Underhill, B. J. Wainwright, A. Aderem, S. Grimmond, and D. A. Hume Generation of Diversity in the Innate Immune System: Macrophage Heterogeneity Arises from Gene-Autonomous Transcriptional Probability of Individual Inducible Genes J. Immunol., January 1, 2002; 168(1): 44 - 50. [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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S.-H. Su, H.-i. Chen, and C. J. Jen C57BL/6 and BALB/c Bronchoalveolar Macrophages Respond Differently to Exercise J. Immunol., November 1, 2001; 167(9): 5084 - 5091. [Abstract] [Full Text] [PDF]
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F.-D. Shi, M. Flodstrom, S. H. Kim, S. Pakala, M. Cleary, H.-G. Ljunggren, and N. Sarvetnick Control of the Autoimmune Response by Type 2 Nitric Oxide Synthase J. Immunol., September 1, 2001; 167(5): 3000 - 3006. [Abstract] [Full Text] [PDF]
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A. S. MacDonald, A. D. Straw, B. Bauman, and E. J. Pearce CD8- Dendritic Cell Activation Status Plays an Integral Role in Influencing Th2 Response Development J. Immunol., August 15, 2001; 167(4): 1982 - 1988. [Abstract] [Full Text] [PDF]
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L. C. Gavrilescu and E. Y. Denkers IFN-{{gamma}} Overproduction and High Level Apoptosis Are Associated with High but Not Low Virulence Toxoplasma gondii Infection J. Immunol., July 15, 2001; 167(2): 902 - 909. [Abstract] [Full Text] [PDF]
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J. Hori and J. W. Streilein Dynamics of Donor Cell Persistence and Recipient Cell Replacement in Orthotopic Corneal Allografts in Mice Invest. Ophthalmol. Vis. Sci., July 1, 2001; 42(8): 1820 - 1828. [Abstract] [Full Text] [PDF]
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V. Iniesta, L. C. Gomez-Nieto, and I. Corraliza The Inhibition of Arginase by N{omega}-Hydroxy-L-Arginine Controls the Growth of Leishmania Inside Macrophages J. Exp. Med., March 19, 2001; 193(6): 777 - 784. [Abstract] [Full Text] [PDF]
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