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*
Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy;
Dipartimento di Patologia, Università di Brescia, Brescia, Italy;
Dipartimento di Patologia, Generale Sezione Patologia Generale, Università degli studi di Verona, Verona, Italy;
§
Dipartimento di Biotechologie Sezione di Patologia Generale Immunologia, Università di Brescia, Brescia, Italy; and
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Research Center Borstel, Borstel, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, become activated
with altered expression of surface Ags and receptors (e.g., Fc
receptors and MHC class II molecules), increased production of
proinflammatory cytokines (e.g., IL-1, IL-6, TNF, and chemokines), and
enhanced capacity to produce reactive oxygen intermediates and kill
intracellular pathogens (1, 2, 3, 4). Alternatively, macrophages
can be activated by IL-4 and IL-13, two Th2 cytokines, and these cells
express a different activated profile consisting in the induction of
the mannose receptor, MHC class II expression, IL-1 receptor
antagonist, and type II IL-1 decoy receptor. On the contrary,
alternative activated macrophages show reduced proinflammatory cytokine
secretion (e.g., IL-1, TNF, IL-6, and chemokines) (2, 5, 6, 7, 8, 9, 10, 11). Although IFN--activated macrophages resemble those
found during the early phases of inflammation, alternative activated
macrophages characterize chronic inflammatory diseases, psoriasis, and
wound healing (2).
Chemokines play a central role in leukocyte extravasation and migration
(12, 13, 14, 15, 16, 17). CC (or ß) chemokines (e.g., members of the
monocyte chemotactic protein, and macrophage inflammatory protein
clusters) are the main agonists for mononuclear leukocytes, including
monocytes, lymphocytes, NK, and dendritic cells. Alternatively, members
of the other major chemokine subfamily, the CXC (or 
) chemokines
(e.g., IL-8, growth-regulated oncogene
(Gro)3 and
IFN--inducible protein-10 (IP-10)) are predominantly recognized as
chemoattractants for neutrophils and lymphocytes (12, 13, 14, 15, 16, 17).
The major factor that dictates chemokine specificity for target cells
is the regulated expression of chemokine receptors. Nine receptors for
CC chemokines (CCR1–9) and five receptors for CXC chemokines
(CXCR1–5) were cloned and characterized. Lymphotactin and fractalkine,
the only representatives of two additional chemokine families, also
bind specific receptors, XCR1 and CX3CR1, respectively (12, 13, 14, 15, 16, 18).
Inflammatory and immune signals are the major inducers of chemokine
production both in vitro and in vivo. Endotoxin, IL-1, and TNF induce
the production both of CC (e.g., monocyte chemotactic protein-1
(MCP-1), MCP-2, MCP-3, and macrophage inflammatory protein-1
(MIP-1)), and CXC (e.g., IL-8, neutrophil activating protein-2
(NAP-2), and Gro) chemokines by many cellular types, including
mononuclear phagocytes and endothelial cells (12, 13, 14, 15, 17).
Of note, proinflammatory agonists also regulate the expression of
chemokine receptors on leukocytes. LPS, TNF, and IFN- were shown to
down-regulate the expression of CCR2, the receptor for MCP-1 to -4, in
monocytes (19, 20) and CXCR1 and CXCR2, the two IL-8
receptors, in human neutrophils (21). Thus, the same
signals generated during an inflammatory response have a reciprocal and
opposite effect on chemokine and chemokine receptor expression on
inflammatory cells, and this may represent an important mechanism to
control chemokine specificity in vivo (12, 17).
The role of IL-4 and IL-13 on the chemokine system is more complex.
Both cytokines were reported to inhibit the LPS-induced expression of
MCP-1, MIP-1, and IL-8 in monocytes, but were ineffective or indeed
synergize the production of the same chemokines in endothelial cells
(11, 12, 17). Furthermore, both IL-4 and IL-13 selectively
induce the expression of certain chemokines, such as macrophage-derived
chemokine (22, 23) and dendritic-cell-derived C-C
chemokine-1 (DC-CK1/AMAC-1/PARC) in monocytes (2, 24, 25).
The effect of these two Th2 cytokines on chemokine receptor expression
in mononuclear phagocytes is presently unknown.
This work was undertaken to investigate whether IL-4 and IL-13, two cytokines that are able to induce a peculiar activation phenotype in mononuclear phagocytes, might also reorient the responsiveness of human monocytes by altering the expression of their chemokine receptor repertoire.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human recombinant MCP-1 was from PeproTech (Rocky Hill, NJ). Human recombinant IL-8 was from Dainippon (Osaka, Japan). Human recombinant Gro-ß and M-CSF were from Cetus (Emeryville, CA). Human recombinant GM-CSF was from Sandoz (Milan, Italy). Human recombinant IL-4 was from Schering-Plough (Kenilworth, NJ), and human IL-13 was a kind gift from Dr. A. Minty (Sanofi Elf Bio Recherches, Labège, France). Cytokines were endotoxin free as assessed by Limulus amebocyte assay.
Cell preparation
Monocytes were obtained from buffy coats of healthy blood donors through the courtesy of Centro Trasfusionale (Ospedale Sacco, Milan, Italy). Blood was washed once with saline and spun at 300 x g to remove plasma and platelets and then centrifuged on Ficoll (Biochrom, Berlin, Germany) at 400 x g for 30 min at room temperature. Monocytes were purified by centrifugation on 46% iso-osmotic Percoll (Pharmacia, Uppsala, Sweden) gradient, as previously described (26). These cells were >95% monocytes as evaluated by morphological analysis. PMN were purified by centrifugation on 63% iso-osmotic Percoll gradient, as previously described (27). These cells were >95% neutrophils as evaluated by morphological analysis. Neutrophil viability in control and IL-4-treated cells was >80% at 24-h culture. Monocyte-derived dendritic cells and CD34+ cell-derived dendritic cells (CD34+-DC) were obtained by culturing in vitro monocyte and cord blood-purified CD34+ cells exactly as previously described (28). Macrophages were obtained incubating monocytes in petriperm dishes (Haereus, Vienna, Austria) for 7 days in RPMI with 10% FCS supplemented with 1000 U/ml M-CSF. Cells (5 x 106/ml) were stimulated with IL-4 and IL-13 in nonadhesion conditions in RPMI 1640 medium (Biochrom) with 10% FCS (HyClone, Logan, UT).
Northern blot analysis
Total RNA was extracted by the guanidinium thiocyanate method,
blotted and hybridized as described (26). Probes were
labeled by Megaprime DNA labeling system (Amersham, Buckinghamshire,
U.K.) with [-32P]dCTP (3000 Ci/mmol,
Amersham). Membranes were prehybridized at 42°C in Hybrisol (Oncor,
Gaithersburg, MD) and hybridized overnight with 1 x
106 cpm/ml of 32P-labeled
probe. Membranes were then washed three times with 2x SSC (1x
SSC = 0.15 M NaCl, 0.015 M sodium citrate, pH 7.0), at room
temperature for 10 min, twice with 2x SSC, 1% SDS at 60°C for 20
min, and then with 0.1x SSC for 5 min, before being autoradiographed
using Kodak (Rochester, NY) XAR-5 films and intensifier screens at
-80°C. Specific CXCR1 probe was obtained with RT-PCR amplifying the
region from 999 to 1341 bp of the reported sequence (GB M68932) with
specific primers (5'-CTCAAGATCCTGGCTATGCATGG-3' and
5'-GAATGATGGTGCTTCGTTTCCATG-3'). Specific CXCR2 probe was
obtained by amplifying the region 995-1415 bp of the reported
sequence (GB M73969) with primers 5'-GGACTCCTCAAGATTCTAGCTATAC-3'
and 5'-GTATGCAGAGCTGTCTCACTGGAG-3'. The extent of the hybridization was
quantified by densitometric analysis with the entry level image system
(Immagini e computer, Milan, Italy).
Migration assay
Cell migration was evaluated using a chemotaxis microchamber technique. Briefly, 27 µl of chemoattractant or control medium (RPMI 1640 with 1% FCS) were added to the lower wells of a chemotaxis chamber (Neuroprobe, Pleasanton, CA) (26, 27). Fifty microliters of cell suspension (1.5 x 106/ml) were seeded in the upper chamber. The two compartments were separated by a polycarbonate filter (5 µm pore size polyvinylpyrrolidone for monocytes and 5 µm pore size polyvinylpyrrolidone free for neutrophils; Neuroprobe). The chamber was incubated at 37°C in humidified atmosphere in the presence of 5% CO2 for 90 min for monocytes and for 60 min for neutrophils. At the end of the incubation, filters were removed and stained, and five high power oil-immersion fields (x100) were counted. Results are expressed as the mean of three replicates ± SD of a single experiment representative of at least three independent donors.
Flow cytometric analysis of CXCR1 and CXCR2 expression
A specific (29) anti-CXCR1 mAb (5A12) was purchased from PharMingen (San Diego, CA). Anti-CXCR2 mAb (RII-115) was obtained as described (30). Monocytes were incubated with saturating amounts of mAbs and with fluorescein-conjugated F(ab')2 goat anti-mouse Ig (Techno Genetics, Turin, Italy). Analysis of fluorescence was performed by a FACStarPlus calibrated with Calibrite Beads (Becton Dickinson, Mountain View, CA).
Nuclear run-off
Nuclear run-off experiments were performed essentially as
described (19, 26). Nuclei were isolated after 18
h of stimulation with IL-13 (20 ng/ml). Then 60 µl of 5x run-off
buffer (25 mM Tris-HCl, pH 8, 12.5 mM MgCl2, 750
mM KCl, and 1.25 mM each of ATP, CTP, and GDP), 2 µl of RNase
inhibitors 1U/µl (Perkin-Elmer/Cetus, Norwalk, CT), and 200 µCi of
[-32P]UTP 3000 Ci/mmol (Amersham) were added
to 220 µl of nuclei suspension and incubated at 30°C for 30 min.
Elongated transcripts were then isolated with the guanidine/cesium
procedure and as described (19). RNA was denatured at
65°C for 5 min and hybridized at 42°C for 48 h to 7 µg of
denatured DNA immobilized on nitrocellulose filters in a few
milliliters of hybridization solution (200 mM
NaHPO4, pH 7.2, 1 mM EDTA, pH 8, 7% SDS, 45%
deionized formamide, and 250 mg/ml yeast tRNA). Filters were then
washed one or two times at 37°C for 20–30 min in 40 mM
NaHPO4-1% SDS and exposed for autoradiography.
Densitometric analysis was performed with the entry level image system
(Immagini e computer), and fold increase was calculated after
ß-actin normalization.
Oxygen free radical production
Monocytes cultured for various time points in the presence or absence of IL-13 or IL-4 (20 ng/ml) were stimulated with 50 ng/ml PMA (Sigma, St. Louis, MO) or with chemokines (1 µg/ml). The production of H2O2 from monocytes was estimated by dihydrorhodamine 123 (DHR) oxidation, as previously described (31).
Electrophoresis and immunoblotting
Proteins were subjected to SDS-PAGE on 12% gels. Proteins were transferred to nitrocellulose membranes (Bio-Rad, Richmond, CA) as previously described (31). Blots were probed with rabbit anti-gp91phox, anti-p22phox, anti-p67phox, anti-p47phox, and anti-p40phox diluted 1:500 at 4°C overnight. Immunoreactive proteins were detected by enhanced chemiluminescence (ECL; Amersham). Multiple exposure of the same blot were performed to ascertain that the ECL signal was in the linear range of sensitivity.
Immunohistochemistry
IL-8 receptor expression was tested by immunohistochemistry on tissue samples from patients suffering from Omenn’s syndrome (two lymph nodes) and atopic dermatitis (one skin biopsy). Lymph node samples showing nonspecific reactive changes and normal skin biopsies were used as controls. Tissues were fresh frozen immediately after biopsy and stored at -80°C until used for immunostaining. mAb 5A12 was used at a dilution of 1:50, and immunoreactivity was developed using a Streptavidin-biotin immunoperoxidase technique, as described (32).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). CXCR3 expression was
detectable neither in resting nor in IL-13-activated cells, whereas the
expression of CXCR4 was slightly reduced in IL-13-activated cells (data
not shown). The induction of CXCR1 and CXCR2 expression was clearly
detectable after 4-h stimulation and became maximal at 24 h (Fig. 1A) with no further increase at 48 h (n
= 2; data not shown). The effect of IL-13 was concentration dependent
reaching a plateau at 20 ng/ml (data not shown), with
EC50 values of 6.2 ± 1 ng/ml and 8.3
± 0.3 ng/ml IL-13 for CXCR1 and CXCR2, respectively (n
= 3; Fig. 1B). IL-4 paralleled the effect of IL-13 both in
terms of concentration curve and kinetics (data not shown). The effect
of IL-13 on CXCR1 and CXCR2 expression was at the transcriptional
level, as assessed by nuclear run-off experiments. Resting monocytes
showed a low rate of transcription of CXCR1 and CXCR2 mRNA.
Transcription of both genes was strongly increased (
20-fold) by
IL-13 treatment (Fig. 1C).
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). At their optimal concentrations (20
ng/ml), the effect of the two cytokines was already detectable after
4-h incubation and reached maximal levels after 24 h with 4.2
± 0.4- and 3.1 ± 0.9-fold of increase over control values for
CXCR1 (n = 4) and CXCR2 (n = 5),
respectively.
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shows that resting monocytes did
not migrate in response to IL-8, a CXCR1 and CXCR2 ligand, and to
Gro-ß a CXCR2 selective ligand (Fig. 3, A and
B). As expected, in the same experimental conditions,
monocytes migrated in response to MCP-1 a chemokine active on monocytes
(Fig. 3C). However, monocytes that had been exposed to IL-13
(20 ng/ml for 24 h) were able to respond to IL-8 in a chemotactic
assay (Fig. 3A). Migration to IL-8 was concentration
dependent with activity already present at 30 ng/ml (3.6 nM) and
reaching a plateau between 100 and 1000 ng/ml (12–120 nM) IL-8. At the
concentration of 300 ng/ml IL-8, the migration of monocytes was 62
± 8% (n = 9) of that observed in response to an
optimal concentration of MCP-1 (50 ng/ml). Similar results were
obtained when IL-4, instead of IL-13, was used (Fig. 3C and
data not shown). Consistent with the kinetics observed by FACS
analysis, migration to IL-8, and to Gro-ß became detectable at 4-h
stimulation with maximal activity observed at 24 h of IL-13/IL-4
stimulation (Fig. 3B and data not shown). Brief (30–60 min)
exposure of monocytes to IL-13/IL-4 did not induce monocyte migration
to IL-8 (data not shown). Basal migration and chemotaxis to MCP-1 were
not modified by IL-13/IL-4 stimulation (Fig. 3C).
Collectively, these results strongly suggest that the effect of IL-13
and IL-4 is not that of a general priming of monocyte migration but
rather that it is mediated by up-regulation of specific IL-8
receptors.
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A shows that resting
monocytes do not release superoxide anions in response to IL-8, but
that this response was inducible in both IL-13- and IL-4-treated
cells. In the early phase of the response (<5 min) the amount of
IL-8-induced H2O2 release
was comparable to that induced by an optimal concentration of phorbol
ester (PMA). However, at longer times of stimulation (>5 min) PMA
action was stronger than IL-8, as expected (Fig. 4B).
Gro-ß (1 µg/ml) was also able to induce a respiratory burst in
IL-4-treated monocytes, although it was a weaker agonist than IL-8
(1.56 and 2.4 nmol/5 min/3 x 106 cells for
Gro-ß and IL-8, respectively; n = 2). In the same
experimental conditions IL-13/IL-4 did not modify the response of
monocytes to PMA, or to MCP-1, a very weak activator of the oxidative
burst in monocytes (36, 37). Short incubations with IL-13
(30–60 min) were not effective in inducing IL-8 response, and a 24-h
incubation of monocytes with IL-13 did not change the protein levels of
p40phox, p47phox,
p67phox, p22phox,
and gp91phox, five components of the NADPH
oxidase enzyme in phagocytes (Fig. 4C) (38, 39). Again, collectively these results strongly suggest that
IL-13 does not induce priming of monocytes for the activation of the
oxidative burst, and that the response to IL-8 is mediated by the
increased number of IL-8 receptors.
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shows that similarly to monocytes
IL-13 up-regulates the expression of IL-8 receptors in monocyte-derived
macrophages. Dendritic cells generated in vitro from both monocytes and
CD34+ precursors express basal levels of CXCR1
and CXCR2 (41, 42), and IL-13 is able to up-regulate this
expression. Interestingly, IL-13 has an opposite effect on neutrophils,
being able to down-regulate IL-8 receptor basal expression
(20-fold). This effect is functionally relevant, because PMN
incubated with 20 ng/ml IL-13 show a significant inhibition in their
chemotactic response to IL-8 (47% inhibition with 100 ng/ml IL-8;
n = 2).
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, A and B). On the
contrary, in Omenn’s syndrome the macrophages and dendritic cells that
typically accumulate within lymph nodes (43) showed strong
reactivity for CXCR1 mAb (Fig. 6C). Similarly, in atopic
dermatitis several CXCR1 immunoreactive mononuclear cells were detected
in the dermis (Fig. 6D). In addition, collections of
mononuclear cells within the epidermis, immunophenotypically identified
as monocyte-derived cells (CD11b+/Mac1,
CD11c+, CD36+,
CD68+) or as immature dendritic cells
(CD1a+) (data not shown) were also recognizable
(Fig. 6E). Finally, anti-IL8 receptor Abs strongly
labeled CD1a+ (data not shown) intraepidermal
cells with obvious dendritic morphology (Fig. 6F).
Unfortunately, neither of the two anti-CXCR2 Abs tested (RII115 and
6C6) reacted in tissue sections, precluding a comparative analysis of
CXCR2 expression in these two pathologies (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-8 is part of a subset of CXC chemokines that share a tripeptide
motif (i.e., Glu-Leu-Arg, ELR) at the NH2
terminus. This group includes, in addition to IL-8, Gro (/ß/),
granulocyte chemotactic protein-2 (GCP-2), epithelial
neutrophil-activating protein-78, NAP-2, and platelet factor-4
(14, 16, 48). IL-8 and GCP-2 activate target cells through
the interaction with both CXCR1 and CXCR2, whereas all the other
members of the group use only CXCR2 (14, 16, 48). Although
CXCR1 and CXCR2 have been described to be expressed by a number of
different leukocyte subsets (e.g., neutrophils, T and B lymphocytes, NK
cells, mast cells, and eosinophils), ELR-CXC-chemokines are considered
to be relevant chemotactic signals only for granulocytes (14, 16, 17, 48). Human monocytes express low levels of surface IL-8
receptors (49, 50, 51), with CXCR2 being more expressed than
CXCR1 (Ref. 50 and Fig. 2
). These receptors can weakly
flux calcium and trigger a weak respiratory burst in Con A-primed
monocytes (47). Nevertheless, IL-8 cannot be considered an
activator of monocyte functions (14, 16, 17, 48, 52, 53).
The observations reported here indicate that freshly isolated human
monocytes do not respond to IL-8 in terms of chemotaxis and release of
oxygen radicals, but that these responses can be readily induced
following exposure to IL-4 and IL-13 and subsequent up-regulation of
CXCR1 and CXCR2. Regulation of chemokine receptor expression by pro-
and anti-inflammatory signals has recently emerged as a key
setpoint for chemokine action (19, 20, 21, 26, 54, 55).
Specifically, CXCR1 and CXCR2 expression were shown to be up-regulated
by G-CSF and down-regulated by LPS, GM-CSF, and TNF- in neutrophils
(21, 56). However, different from all the previous
reports, the effect of IL-13 on CXCR1 and CXCR2 was at the level of
gene transcription rather than on mRNA stability (19, 20, 26, 54, 57, 58). Very recently it was reported that IL-8 can induce firm
adhesion of monocytes to vascular endothelium under flow conditions
(59), and that CXCR2 may mediate the accumulation of
macrophages in atherosclerotic lesions of low density lipoprotein
receptor-deficient mice (60). The present study extends
these observations and supports a role for ELR-chemokines in the
recruitment and activation of mononuclear phagocytes in pathological
conditions in which IL-4 and IL-13 are expressed, such as Th2 immune
responses (61).
This hypothesis is supported by the demonstration that monocyte-derived cells and dendritic cells express IL-8 receptors in Omenn’s syndrome and atopic dermatitis, two pathological conditions typically characterized by a Th2-dominated immune response and IL-4 production (43, 44, 61).
IL-8 has been shown to be an important mediator of chronic inflammatory diseases like allergic bronchial asthma, rheumatoid arthritis, and psoriasis (62, 63, 64). In vivo, neutrophils predominate at early stages of inflammation, whereas monocytes and lymphocytes characterize late inflammatory phase reactions and chronic inflammation (65). Interestingly, we found that IL-4 and IL-13 down-regulate CXCR1 and CXCR2 expression in neutrophils and reduce their ability to migrate in response to IL-8. This evidence is confirmed in vivo in a mouse model of acute lung injury in which exogenously administered IL-13 reduces neutrophil counts in bronchoalveolar fluids, whereas an anti-IL-13 Ab has an opposite effect in mice administered IgG immune complexes (66). IL-13 down-regulates the expression of ICAM-1 in vascular endothelium (40, 67). ICAM-1/ß2 integrin interaction is a crucial event for neutrophil endothelial cell transmigration in vitro and neutrophil recruitment in vivo (68, 69). On the contrary, IL-13 up-regulates the expression of VCAM-1, the counterreceptor of very late Ag-4, a ß1 integrin expressed by monocytes and eosinophils and relevant for their interaction with cytokine-activated endothelium (67, 70, 71). IL-13 and IL-4 can act in synergism with TNF to promote the secretion of IL-8 by human endothelial cells (67, 72, 73). Collectively, it is tempting to speculate that IL-13 and IL-4 can trigger a biological program that reorients the action of IL-8 from neutrophils to monocytes and contributes to the formation of the mononuclear phagocyte infiltrate that characterize chronic inflammatory lesions. In this respect it is interesting to note that IL-8 is expressed by lesional macrophage-derived foam cells (74), and KC/Gro is present in atherosclerotic lesions (60).
The leukocyte infiltrate of IL-13-secreting tumors has a major mononuclear phagocyte component (75). It is tempting to speculate that IL-13 might act directly in the recruitment of monocytes for its chemotactic activity (76), or by inducing the expression of IL-8 receptors on these effector cells.
IL-8 and related CXC chemokines have long been known to be selective neutrophil attractants in vitro and in vivo (53, 77, 78), with little or no effect on monocytes. The results presented in this paper show that IL-4 and IL-13 convert ELR+ CXC chemokines into potent monocyte attractants by up regulating receptor expression. Furthermore, this study reports that two Th2 pathologies characterized by the presence of IL-4 and IL-13 are characterized by an infiltrate of IL-8 receptor positive mononuclear cells. Therefore, IL-8 and other CXC chemokines, whose production is weakly induced in endothelial cells by IL-4 and IL-13, may contribute to the accumulation and positioning of alternatively activated macrophages in Th2-dominated responses (2, 61).
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Silvano Sozzani, Istituto di Ricerche Farmacologiche "Mario Negri," via Eritrea 62, 20157 Milan, Italy. E-mail address:
3 Abbreviations used in this paper: Gro, growth-regulated oncogene; IP-10, IFN- inducible protein-10; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; NAP, neutrophil activating protein; ELR, Glu-Leu-Arg.
Received for publication November 4, 1999. Accepted for publication January 14, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]
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P. L. Podolin, B. J. Bolognese, J. J. Foley, D. B. Schmidt, P. T. Buckley, K. L. Widdowson, Q. Jin, J. R. White, J. M. Lee, R. B. Goodman, et al. A Potent and Selective Nonpeptide Antagonist of CXCR2 Inhibits Acute and Chronic Models of Arthritis in the Rabbit J. Immunol., December 1, 2002; 169(11): 6435 - 6444. [Abstract] [Full Text] [PDF]
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 S L Traves, S V Culpitt, R E K Russell, P J Barnes, and L E Donnelly Increased levels of the chemokines GRO{alpha} and MCP-1 in sputum samples from patients with COPD Thorax, July 1, 2002; 57(7): 590 - 595. [Abstract] [Full Text] [PDF]
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J. M. Schuh, K. Blease, and C. M. Hogaboam CXCR2 Is Necessary for the Development and Persistence of Chronic Fungal Asthma in Mice J. Immunol., February 1, 2002; 168(3): 1447 - 1456. [Abstract] [Full Text] [PDF]
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M. Thivierge, J. Stankova, and M. Rola-Pleszczynski IL-13 and IL-4 Up-Regulate Cysteinyl Leukotriene 1 Receptor Expression in Human Monocytes and Macrophages J. Immunol., September 1, 2001; 167(5): 2855 - 2860. [Abstract] [Full Text] [PDF]
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G. Penna, S. Sozzani, and L. Adorini Cutting Edge: Selective Usage of Chemokine Receptors by Plasmacytoid Dendritic Cells J. Immunol., August 15, 2001; 167(4): 1862 - 1866. [Abstract] [Full Text] [PDF]
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A. Zernecke, K. S. C. Weber, L. P. Erwig, D. C. Kluth, B. Schroppel, A. J. Rees, and C. Weber Combinatorial Model of Chemokine Involvement in Glomerular Monocyte Recruitment: Role of CXC Chemokine Receptor 2 in Infiltration During Nephrotoxic Nephritis J. Immunol., May 1, 2001; 166(9): 5755 - 5762. [Abstract] [Full Text] [PDF]
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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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