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*
Immunopharmacology, Departamento de Bioquímica e Imunologia, Instituto Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;
Departmento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, Fundaçao Oswaldo Cruz, Rio de Janeiro, Brazil;
Serono Pharmaceuticals, Geneva, Switzerland; and
Department of Pathology, University of Michigan, Ann Arbor, MI 48109
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(MIP-1) induced a time- and dose-dependent eosinophil recruitment.
Pretreatment with anti-eotaxin, but not anti-RANTES or
anti-MIP-1, blocked the recruitment of eosinophils following Ag
challenge of sensitized animals, and significant eotaxin
immunoreactivity was detected in the pleural cavity of these animals.
Similarly, only the anti-eotaxin inhibited the eosinophil
recruitment induced by injection of SCF in naive animals. However,
blockade of SCF did not inhibit the release of eotaxin after Ag
challenge of sensitized mice. Akin to its effects on SCF and in the
allergic reaction, eotaxin-induced eosinophil recruitment was blocked
by the LTB4 receptor antagonist CP105696. Nevertheless,
SCF, but not eotaxin, appeared to regulate the endogenous release of
LTB4 after Ag challenge. Finally, we show that low doses of
eotaxin synergized with LTB4 to induce eosinophil
recruitment in the pleural cavity. Overall, the present results show
that eotaxin and SCF-induced LTB4 cooperate to induce
eosinophil recruitment into sites of allergic inflammation. Cooperation
between inflammatory mediators must be an important phenomenon in vivo,
explaining both the ability of lower concentrations of mediators to
induce a full-blown functional response and the effectiveness of
different strategies at inhibiting these
responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The activation of eosinophils via G protein-coupled seven transmembrane receptors with subsequent increase in intracellular calcium and up-regulation of integrin-mediated adhesion play a necessary role in the recruitment of these cells into tissue (4, 5, 6). Chemokines are among the mediators known to activate eosinophil recruitment via activation of a growing family of G protein-coupled receptors, the chemokine receptors (7). These low molecular mass cytokines are produced in several chronic inflammatory diseases, including asthma, and are thought to be major modulators of leukocyte trafficking in health and disease (8). As such, the development of drugs or proteins which antagonize chemokine receptors may represent a novel strategy in the treatment of allergic and other inflammatory diseases.
We have recently shown a role for stem cell factor (SCF)4 in mediating eosinophil recruitment in an allergic pleurisy model in mice via the local production of the chemoattractant lipid leukotriene B4 (LTB4) (9). However, chemokines have also been shown to play an important role in mediating eosinophil recruitment in various models of allergic inflammation (10, 11), and we have previously shown an essential role of eotaxin for the recruitment of eosinophils during allergic inflammation in murine skin (5). Thus, it was of interest to investigate whether chemokines participated in the cascade of events leading to eosinophil recruitment in our allergic pleurisy model. In particular, we were interested in examining whether chemokines would act directly or indirectly, via the release of LTB4, to induce eosinophil recruitment in vivo. Here, we demonstrate that eotaxin and SCF-induced LTB4 cooperate to induce eosinophil recruitment in an allergic inflammatory response in mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male BALB/C mice (18–22 g) were used throughout these experiments. Animals were housed in a temperature-controlled room with free access to water and food. All experimental protocols have been subjected to evaluation by the local Animal Ethics Committee.
Drugs and reagents
Recombinant murine chemokines and murine SCF were purchased from PeproTech (London, U.K.). The chemokine receptor antagonist Met-RANTES was synthesized in-house as previously described (12). Chemokines, SCF, or Met-RANTES were dissolved in water, diluted further in PBS (pH 7.4) containing 0.01% BSA, and stored at -20°C until use. Endotoxin levels in all solutions were <0.1 ng/µg protein (maximal injection into the peritoneal cavity of contaminating LPS was 0.01 ng) and was much lower than the dose of endotoxin needed to induce eosinophil migration in the model (>50 ng/cavity). BSA, OVA, and control rabbit serum were purchased from Sigma (St. Louis, MO). The LTB4 receptor (BLT) antagonist CP105696 was a gift from Pfizer/Groton Laboratories (Groton, CT). CP105696 was dissolved in DMSO and further diluted in saline. The final concentration of DMSO in the solution was lower than 1%. Control animals received drug vehicle.
Anti-chemokine Abs
Antimacrophage-inflammatory protein 1 (MIP-1),
anti-RANTES, or anti-eotaxin Abs were prepared by immunizing
rabbits with recombinant murine MIP-1, RANTES, or eotaxin as
previously described (13, 14, 15). The IgG portion of the
serum of hyperimmune or preimmune rabbits was purified over a protein A
column (Pierce, Rockford, IL) and stored at -20°C in PBS until
use.
Sensitization
Animals were immunized with OVA adsorbed to aluminum hydroxide gel as previously described (16). Briefly, mice were injected s.c. on days 1 and 8 with 0.2 ml of a solution containing 100 µg of OVA and 70 µg of aluminum hydroxide (Reheiss, Dublin, Ireland).
Leukocyte migration into the pleural cavity induced by MIP-1,
RANTES, eotaxin, or LTB4
Recombinant murine MIP-1, RANTES, eotaxin (10, 30, and 100
ng/pleural cavity, respectively) or
LTB4 (15-500 ng/cavity)
were injected intrapleurally (i.pl.) in naive mice, and animals were
killed at different times (4, 24, 48, or 72 h) after the i.pl.
injection of the chemokines. In some experiments, eotaxin and
LTB4 were mixed before their i.pl. injection. The
cells present in the pleural cavity were harvested by injecting 2 ml of
PBS and total cell counts were performed in a modified Neubauer chamber
using Turk’s stain. Differential cell counts were performed on
cytospin preparations (Shandon III) stained with May-Grunwald-Giemsa
using standard morphologic criteria to identify cell types. The results
are presented as the number of cells per cavity.
Anti-chemokine treatment
The role of endogenous chemokines on the eosinophil recruitment
induced by SCF (100 ng/cavity) or in the allergic pleurisy (1 µg of
Ag into sensitized animals) was investigated by using
anti-MIP-1, anti-RANTES, anti-eotaxin, or control IgG. A
total of 100 µg of purified Abs was injected i.p. 30 min before the
administration of Ag or SCF. Eosinophil migration was evaluated 48
h after the inflammatory stimuli. As positive controls, each specific
anti-chemokine Ab was tested with the relevant chemokine against
which it was raised.
Measurement of LTB4 and eotaxin
Frozen supernatants obtained from pleural cavity washes at different times (1–24 h) after challenge with OVA, SCF, and PBS were used for eotaxin detection. In some experiments, a rabbit anti-murine SCF polyclonal Ab or rabbit IgG (all at 100 µg/mice) were injected i.p. 30 min before Ag challenge. Six hours later, the pleural cavity was washed and the levels of eotaxin were assessed on the supernatant.
The level of eotaxin protein in pleural effluents was measured by specific ELISA as reported elsewhere (17). Briefly, flat-bottom 96-well microtiter plates (Costar, Cambridge, MA) were coated with 100 µl/well of anti-murine eotaxin polyclonal Ab (R&D Systems, Minneapolis, MN), left overnight at room temperature (RT), and then washed with an assay wash solution containing 1 M phosphate/potassium buffer (pH 7.5) added with thimerosal (0.2 mg/ml) and 0.05% Tween 20. Nonspecific binding sites were blocked with 1% BSA in PBS and incubated for 1 h at RT. Plates were washed four times with wash buffer and cell-free supernatants were added followed by incubation at RT for 1 h. After washing the plate four times, a biotinylated rabbit polyclonal Ab specific for murine eotaxin (R&D Systems) was added, and the plates were incubated for 1 h at RT. After washing, the neutroavidin-HRP conjugate (Bio-Rad, Richmond, CA) was added, and plates were incubated for 1 h at RT. After the last plate washing, 100 µl/well of the chromogen substrate (K-blue; Neogen, Lansing, MI) was added and incubated at RT for 30 min. The reaction was stopped with 100 µl/well of 0.19 M H2SO4 solution, and the plates were read at 450 nm. Standards were 1:2 dilutions of recombinant murine eotaxin ranging from 5 to 640 pM. No cross-reaction with other known C-C chemokines was noted.
Frozen supernatants from the pleural cavity of animals injected with eotaxin were also assayed for LTB4 levels. Moreover, LTB4 levels were also detected 8 h after Ag challenge in control (rabbit IgG), anti-SCF-treated, or anti-eotaxin-treated mice (all 100 µg/mice). For these experiments, pleural cavities were lavaged with 0.5 ml of ice-cold PBS and immediately frozen and stored at -70°C until the assay was performed. LTB4 was determined using a specific LTB4 ELISA detection kit (R&D Systems) according to the instructions of the manufacturer.
LTB4 receptor antagonist pretreatment
To investigate the role of endogenous LTB4 on the eosinophil recruitment induced by eotaxin, the LTB4 receptor antagonist CP105696 (18, 19) was administered i.p. 60 min before eotaxin at the dose of 3 mg/kg, and the number of infiltrating eosinophils was assessed 4 or 48 h later.
Met-RANTES treatment
Met-RANTES (5 or 30 µg) was administered i.p. 24 and 1 h before the injection of eotaxin or SCF in naive mice or OVA in immunized mice. Animals were killed 48 h later and the number of eosinophils recruited to the cavity was evaluated.
Immunohistochemical analysis for eotaxin
Pleural washes were obtained 6 h after the challenge with OVA in naive or immunized mice. The samples were centrifuged, the resulting pellet resuspended in PBS containing 3% BSA, and cytospins containing 5 x 104–105 cells prepared. Slides were fixed in ice-cold acetone for 10 min and stored at -70°C until use. Slides were then placed in a humidified chamber and endogenous peroxidase activity was blocked with 3% hydrogen peroxide for 40 min followed by three washes with PBS. Samples were pretreated with rabbit serum (5%) for 60 min and incubated overnight with a polyclonal rabbit anti-mouse eotaxin (1:400 dilution). After three washes in PBS, biotinylated goat anti-rabbit Ig (Dako, Carpinteria, CA) were added for 40 min and then incubated with streptavidin-peroxidase for 40 min. The reaction product was detected with diaminobenzidine in H2O2 buffer (Dako) and slides counterstaining with Harry hematoxylin. Controls were performed by incubating cells with preimmune rabbit serum and proceeding as describe above.
Statistical analysis
All results are presented as the mean ± SEM. Normalized data were analyzed by one-way ANOVA, and differences between groups were assessed using the Student-Newman-Keuls posttest. A value of p < 0.05 was considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Initial experiments were designed to test the ability of the
eosinophil-active chemokines MIP-1, RANTES, and eotaxin to induce
eosinophil recruitment into the pleural cavity of naive mice. The i.pl.
injection of eotaxin or MIP-1 induced the recruitment of eosinophils
48 h after injection only when given at the highest dose tested
(100 ng/site), whereas RANTES-induced responses were maximal at a three
times lower dose (Fig. 1
).
Eotaxin-induced eosinophil recruitment was fast in onset (already
noticeable 4 h after its injection) and long-lasting with
significant cell influx after 72 h (Fig. 1F). MIP-1-
and RANTES-induced responses were slower in onset and peaked after
48 h (Fig. 1, D and E). Eosinophilia after
RANTES injection was completely resolved after 72 h (Fig. 1E).
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Since all three chemokines were effective at inducing eosinophil
recruitment when injected into the pleural cavity of mice, we examined
whether blockade of chemokines would interfere with the eosinophil
recruitment following Ag challenge of immunized mice. As seen in Fig. 2A, pretreatment with
anti-MIP-1 or anti-RANTES polyclonal Abs pretreatment failed
to inhibit the eosinophil recruitment induced by Ag injection in
sensitized animals. In contrast, at the dose used (100 µg/mouse), the
Abs could significantly block the recruitment of leukocytes induced by
the chemokines against which they were raised (Table I). Pretreatment with anti-eotaxin
significantly blocked the eosinophil recruitment induced by Ag
challenge in sensitized mice by 77% (Fig. 2A). In support
of an important role for the endogenous production of eotaxin for the
recruitment of eosinophils during allergic inflammation, significant
levels of eotaxin could be detected in the pleural cavity of sensitized
mice after Ag challenge. Eotaxin was already detectable at 1 h
after Ag challenge and peaked at 6 h with levels dropping
thereafter (Fig. 2B). Immunohistochemistry of leukocytes
obtained from pleural washes of sensitized animals 6 h after Ag
challenge showed that most eotaxin immunoreactivity was detected in
mononuclear cells, especially macrophages (Fig. 2C).
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A, SCF-induced
eosinophil recruitment was significantly inhibited by pretreatment with
anti-eotaxin (74% inhibition), but not with anti-MIP-1 or
anti-RANTES. Similarly to the allergic reaction, eotaxin was also
detected in the supernatant obtained from the pleural cavity of
SCF-injected naive mice (Fig. 3B). SCF-induced eotaxin was
early in onset (1 h) and of shorter duration, peaking at 3 h and
dropping to background levels by 6 h (Fig. 3B).
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Pretreatment with the chemokine receptor antagonist Met-RANTES, 24
and 1 h before i.pl. injection of the inflammatory stimuli,
significantly inhibited the recruitment of eosinophils induced by SCF,
OVA, and eotaxin (Fig. 4). Whereas a dose
of 5 µg/mouse of Met-RANTES failed to inhibit eotaxin-induced
eosinophil recruitment significantly, it suppressed the eosinophil
recruitment following SCF injection and in the allergic reaction (Fig. 4). When given at 30 µg/mouse, Met-RANTES significantly suppressed
eotaxin-induced eosinophil recruitment (Fig. 4).
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High levels of LTB4 are detected after
injection of SCF and in the allergic pleurisy and appears to be an
important mediator of eosinophil recruitment in mice (9).
Since eotaxin is also released in allergic pleurisy and is capable of
inducing eosinophil recruitment, we tested whether eotaxin was an
intermediate for the generation of LTB4 in the
allergic pleurisy and whether LTB4 played a role
in eotaxin-induced eosinophil recruitment. Fig. 5A shows the effects of the
pretreatment with anti-eotaxin or anti-SCF Abs in the
generation of LTB4 6 h following Ag
challenge of sensitized mice. Whereas pretreatment with
anti-eotaxin Ab failed to inhibit the production of
LTB4 induced by OVA challenge in sensitized mice,
pretreatment with anti-SCF virtually abrogated the generation of
LTB4 (Fig. 5A). Although background
levels were high and potentially in the range for biological activity
in murine eosinophils, levels in OVA-challenged mice were eight times
greater than background (Fig. 5A). In contrast to the
effects of the challenge with SCF or OVA (9),
LTB4 levels above background were not detectable
from 1 to 48 h after eotaxin injection in naive mice (Fig. 5B).
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A). Similarly, eosinophil
recruitment assessed 4 h after eotaxin was inhibited by 60% (Fig. 6A). This was a surprising result because eotaxin appeared
not to induce detectable levels of LTB4 under our
assay conditions. In contrast, the pretreatment with anti-eotaxin
had no significant effect on the eosinophil recruitment induced by the
i.pl. injection of LTB4 (Fig. 6B),
demonstrating that LTB4-induced eosinophil
recruitment is independent of eotaxin.
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, coinjection of eotaxin and LTB4 induced a
recruitment of eosinophils that was greater than the action of each
mediator when injected alone.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The i.pl. injection of MIP-1, RANTES, or eotaxin induced a
significant dose-dependent accumulation of eosinophils 48 h after
challenge. The effects of MIP-1 and eotaxin are in agreement with
previous studies demonstrating the ability of these chemokines to
induce eosinophil recruitment directly, by activating specific
receptors on eosinophils, or indirectly, by activating intermediate
cell types, such as mast cells (5, 21, 22, 23). In contrast,
RANTES does not appear to stimulate murine (24) or guinea
pig (25) eosinophils directly, suggesting that the ability
of this chemokine to induce eosinophil migration most likely depends on
its action on an intermediate cell type. However, only endogenous
production of eotaxin appeared to play a role in mediating eosinophil
recruitment after Ag challenge of sensitized animals. In support of an
important role of eotaxin, significant eotaxin protein, but not
MIP-1 or RANTES (data not shown), could be detected in pleural
washes after Ag challenge. Moreover, eotaxin immunoreactivity was
detected in pleural cavity cells, especially in macrophages. These
results are in agreement with other studies demonstrating a role for
eotaxin in mediating eosinophil recruitment in models of allergic
inflammation in vivo (5, 10, 26, 27, 28). Blockade of
endogenous eotaxin, but not of RANTES or MIP-1, resulted in
significant inhibition of SCF-induced eosinophil migration and SCF also
induced significant eotaxin generation in pleural washes. This is an
interesting finding because we have previously shown that SCF played a
major role in driving eosinophil recruitment after Ag challenge
(9). However, pretreatment with anti-SCF failed to
alter the levels of eotaxin immunoreactivity after challenge of
sensitized mice with OVA. Thus, although SCF can induce eotaxin when
injected into naive mice and the endogenously generated eotaxin plays a
role in the SCF-induced effects, SCF does not drive the production of
eotaxin following Ag challenge in an allergic reaction.
Pretreatment of animals with the broad-acting chemokine receptor antagonist Met-RANTES inhibited the recruitment of eosinophils induced by eotaxin, induced by SCF, or in the allergic reaction. Of note, eotaxin-induced responses were only significantly inhibited when higher doses of Met-RANTES were given. These results are in agreement with our previous studies demonstrating a small, but significant inhibitory effect of high concentrations of Met-RANTES on murine CCR3 activation (5, 29, 30). Altogether, our results show that blockade of chemokine receptors with Met-RANTES is an effective strategy to block eosinophil recruitment. The ability of Met-RANTES to inhibit eosinophil influx at a dose smaller than necessary to block eotaxin-induced eosinophil recruitment suggests that chemokine receptors in addition to CCR3 may be involved in the inhibitory effects observed. In support of the latter suggestion, previous studies have demonstrated a role for chemokines such as monocyte chemoattractant protein 5 and macrophage-derived chemokine, which bind to receptors other than murine CCR3 in mediating eosinophil influx in an allergic reaction (31, 32).
We have previously shown that LTB4 is an effective direct inducer of eosinophil recruitment in several species (5, 33, 34). In our model, there is a marked generation of LTB4 following Ag challenge of sensitized mice or the injection of SCF into naive mice (9). Not only is LTB4 generated, but the pretreatment with the LTB4 receptor (BLT) antagonist CP105696 effectively inhibited eosinophil recruitment following Ag challenge or injection of SCF (9). Since the latter stimuli also induce eotaxin generation, we set out to investigate how eotaxin cooperated with LTB4 to mediate eosinophil recruitment in vivo. Injection of eotaxin induced no detectable amounts of LTB4 in the pleural cavity and pretreatment with anti-eotaxin had no effect on the levels of LTB4 following Ag challenge of sensitized animals. Unexpectedly, pretreatment of animals with CP105696 abrogated the recruitment of eosinophils following injection of eotaxin into the pleural cavity of naive mice. At present we do not have a good explanation for these discrepant results. We have only measured LTB4 levels in the pleural wash fluid and not in pleural and lung tissue, the microenvironments from where eosinophils migrate. Thus, it is possible that eotaxin does indeed induce small quantities of LTB4 that we cannot measure using the methodology described here. As for the inability of eotaxin to drive OVA-induced LTB4 secretion, it is likely that other inflammatory mediators released during the allergic pleurisy, especially SCF, are sufficient to drive the production of LTB4 that is measured in the pleural fluid. Indeed and in contrast to the lack of effect of anti-eotaxin on LTB4 levels, pretreatment with anti-SCF abrogated LTB4 immunoreactivity in pleural cavity washes following Ag challenge. In agreement with our studies, Harris et al. (35) have also demonstrated a role for 5-lipoxygenase-derived mediators in driving eosinophil influx following i.p. injection of eotaxin in mice. LTB4 levels were not measured in the latter study but the authors suggested a role for mast cells in producing LTB4. Interestingly, Marleau et al. (36) have shown that a 5-lipoxygenase-derived lipid, possibly LTB4, was essential for the in vivo recruitment of polymorphonuclear leukocytes following stimulation with a range of mediators. Thus, it is possible that eotaxin may induce LTB4 production in the migrating eosinophils and inhibition of BLT receptors may prevent these cells from migrating. In this respect, an essential role for lipoxygenase metabolites for the chemotactic activity of eosinophils stimulated by RANTES has been previously reported (37). Overall, these results argue for an important role for LTB4 in the recruitment of eosinophils into the pleural cavity of mice. LTB4 may be acting not only as a chemoattractant mediator present after Ag challenge in the pleural cavity but also by activating eosinophils before their migration in vivo (36, 37). However, additional studies are necessary to confirm the latter possibility, especially in human eosinophils which, in contrast to murine eosinophils, lack LTA4 hydrolase and do not appear to secrete appreciable amounts of LTB4 (38, 39). Moreover, it appears that SCF, but not eotaxin, drives the release of LTB4 into the pleural cavity after Ag challenge of sensitized animals.
One final interesting observation was the additive effect of LTB4 and eotaxin to induce the recruitment of eosinophils in vivo. To our knowledge, this is the first observation that demonstrates the cooperation between a lipid mediator and a chemokine to induce eosinophil recruitment and suggests that these mediators may be acting on different signaling pathways to induce the recruitment of eosinophils. These results also suggest that in an allergic reaction, smaller quantities of different mediators (in the present case LTB4 and eotaxin) may be necessary and sufficient to mediate a full recruitment of inflammatory cells. Thus, although mediator redundancy does occur in vivo, a range of different mediators must cooperate to obtain a final adequate response, i.e., eosinophil migration. In addition, mediator cooperation must be an underlying reason explaining the ability of different strategies to inhibit almost maximally different functional responses. In this line of thinking, either anti-SCF or anti-eotaxin are effective at abrogating eosinophil migration in our model because SCF-induced LTB4 may cooperate with eotaxin to induce the total number of eosinophils observed after Ag challenge. If either is absent, the response will not occur or will be severely reduced.
In conclusion, we show a major role for eotaxin in mediating eosinophil recruitment in the allergic pleurisy model. Eotaxin release is not dependent on SCF and does not induce significant LTB4 production, but its action is significantly impaired by the blockade of LTB4 receptors, possibly on the migrating leukocyte. In contrast, SCF is largely responsible for the local release of LTB4 which appears to cooperate with eotaxin to induce the final recruitment of eosinophils observed in the allergic reaction. Cooperation between inflammatory mediators must be an important phenomenon in vivo, explaining both the ability of lower concentrations of mediators to induce a full-blown functional response and the effectiveness of different strategies at inhibiting these responses. Finally, our results suggest that blockade of chemokine receptors and/or BLT receptors may be useful strategies to be pursued for the treatment of allergic diseases in which eosinophils appear to play a major functional role.
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Footnotes |
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2 A.K. is on leave from the Universidade Federal do Mato Grosso do Sul.
3 Address correspondence and reprint requests to Dr. Mauro Martins Teixeira, Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627 Pampulha, 31270-901 Belo Horizonte, Minas Gerais, Brazil. E-mail address: mmtex{at}icb.ufmg.br
4 Abbreviations used in this paper: SCF, stem cell factor; LTB4, leukotriene B4; MIP-1, macrophage-inflammatory protein 1; i.pl., intrapleurally; RT, room temperature; BLT, LTB4 receptor.
Received for publication February 5, 2001. Accepted for publication April 30, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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