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in Human Neutrophils1
*
Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy;
Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, Geneva, Switzerland;
LeukoSite Inc., Cambridge, MA; and
§
Università di Brescia, Brescia, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, a prototypic Th1
cytokine, on chemokine receptor expression in PMN was investigated.
IFN- caused a rapid (
1 h) and concentration-dependent increase of
CCR1 and CCR3 mRNA. The expression of CCR2, CCR5, and CXCR1–4 was not
augmented. IFN--treated PMN, but not control cells, expressed
specific binding sites for labeled monocyte-chemotactic protein (MCP)-3
and migrated to macrophage-inflammatory protein (MIP)-1
, RANTES,
MCP-3, MIP-5/HCC2, and eotaxin. 7B11, a mAb for CCR3, inhibited the
chemotactic response of IFN--treated PMN to eotaxin, and
aminoxypentane-RANTES blocked PMN migration to RANTES. These
results suggest that the selectivity of certain chemokines for their
target cells may be altered by cytokines produced within an
inflammatory context. Since PMN may play a role in orienting immunity
toward Th1 responses, it is possible to speculate that IFN- not only
promotes Th1 differentiation directly, but also reorients the
functional significance of Th2 effector cytokines by broadening the
spectrum of their action to include PMN. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the last decade, a superfamily of chemoattractant proteins named
chemokines has been described. These have a certain degree of
selectivity for different leukocyte populations (2, 4, 5, 6, 7). These
proteins can be sorted into four groups depending on the number and
spacing of conserved cysteines. CXC (or ) chemokines are active on
neutrophils (polymorphonuclear leukocytes;
PMN)4 and T lymphocytes,
while CC (or ß) chemokines exert their action on multiple leukocyte
subtypes, including monocytes, basophils, eosinophils, T lymphocytes,
dendritic cells, and NK cells, but they are generally inactive on PMN.
Eotaxin (CC) represents the chemokine with the most restricted spectrum
of action being selectively active on eosinophilic and basophilic
granulocytes. Lymphotactin and fractalkine, or neurotactin, are the
only proteins so far described for the C and CX3C
chemokines, respectively. They both act on lymphoid cells (T
lymphocytes and NK cells), and fractalkine is also active on PMN (2, 4, 5, 6, 7).
Chemokines interact with G protein-coupled seven-transmembrane domain receptors (4, 8). Five human CXC receptors, named CXCR1 to 5, and nine human CC chemokine signaling receptors (CCR1 to 9) have been reported (4, 6, 7). The pattern of expression of chemokine receptors is the major factor that dictates the selectivity of chemokines for different target cells.
Emerging evidence indicates that chemokine receptors can be
modulated by inflammatory and anti-inflammatory signals. Regulation
of the expression of chemokine receptors may be crucial as a set point
for regulation of the chemokine action, but it has been the object of
limited attention. IL-2 has been reported to induce both CCR1 and CCR2
in T lymphocytes and NK cells (9, 10), and granulocyte-CSF (G-CSF) was
shown to up-regulate CXCR1 and CXCR2 in PMN (11). However,
proinflammatory agonists, such as TNF, IL-1, and LPS, down-regulated
CCR2 in human monocytes (12) and IL-8 receptors in PMN (11). On the
contrary, IL-10, an anti-inflammatory cytokine, up-regulated CCR1,
CCR2, and CCR5 in human monocytes (13). These studies indicate that
locally produced cytokines may regulate the kinetics and the
composition of leukocyte infiltrate at the level of both chemokine
production and chemokine receptor expression. In this study we report
the effect of IFN-, a prototypic Th1 cytokine, on the expression of
chemokine receptors in PMN.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human recombinant monocyte-chemotactic protein (MCP)-1,
macrophage-inflammatory protein (MIP)-1ß, and eotaxin were from
PeproTech (Rocky Hill, NJ). Human recombinant IL-8 was from Dainippon
(Osaka, Japan). Human recombinant MCP-3 and human MIP-1 were a kind
gift from Dr. A. Minty (Sanofi Elf Bio Recherches, Labège,
France) and Dr. L. Czaplewski (British Biotechnology, Cowley, U.K.),
respectively. RANTES and MIP-5/HCC2 (14) were chemically
synthesized (15). IFN- (sp. act. 20 x 106 U/ml)
was obtained from Roussel Uclaf (Romainville, France). Cytokines were
endotoxin-free as assessed by Limulus Amebocyte assay. FMLP was from
Sigma (St. Louis, MO).
Cell preparation
PMN were obtained from buffy coats of healthy blood donors
through the courtesy of Centro Trasfusionale, Ospedale Sacco (Milan,
Italy) by Ficoll (Biochrom, Berlin, Germany) and Percoll (63%
iso-osmotic; Pharmacia, Uppsala, Sweden) centrifugation, as previously
described (16). These cells were >95% neutrophils as evaluated by
morphological analysis. Eosinophil contamination was <1%. In some
experiments, PMN were further purified by sorting CD16+
(mAb KD1; IgG2a, kindly provided by E. Ciccone, Istituto dei Tumori,
Genova, Italy) using a FACStar (Becton Dickinson, Mountain View, CA).
Cells (5 x 106/ml) were resuspended in RPMI 1640
medium (Biochrom) with 10% FCS (HyClone, Logan, UT) and incubated in
petriperm dishes (Haereus, Austria) with different concentrations of
IFN- as specified in the text. Cell viability in control and
IFN--treated cells was >90% up to 8-h culture, and at 24 h it
was 75 ± 8% and 93 ± 5% for control and stimulated PMN,
respectively.
Migration assay
Cell migration was evaluated using a chemotaxis microchamber technique as previously described (17). Twenty-seven microliters of chemoattractant solution, or control medium (RPMI 1640 with 1% FCS), were added to the lower wells of a chemotaxis chamber (Neuroprobe, Pleasanton, CA). A polyvinylpyrrolidone-free polycarbonate filter (5-µm pore size; Neuroprobe) was layered onto the wells and covered with a silicon gasket and with the top plate. Fifty microliters of cell suspension (1.5 x 106/ml PMN) were seeded in the upper chamber. The chamber was incubated at 37°C in air with 5% CO2 for 60 min. At the end of the incubation, filters were removed and stained with Diff-Quik (Baxter, Rome, Italy), and five high-power oil-immersion fields were counted.
Northern blot analysis
PMN were prepared as described above, and total RNA was
extracted by the guanidinium thiocyanate method, blotted, and
hybridized as described (10). Probes were labeled by Megaprime DNA
labeling system (Amersham, Buckinghamshire, U.K.) with
[32P]dCTP (3000 Ci/mmol, Amersham). cDNA probes were
obtained and used as previously reported (10, 12, 13).
Receptor expression analysis
Binding assays were conducted as described previously (17).
Competition for the binding of [125I]MCP-3 and
[125I]eotaxin (sp. act. 2200 Ci/mmol; DuPont de Nemours,
Dreieich, Germany) to PMN (1 x 106/200 µl) was
performed in binding medium (RPMI 1640 with 10 mg/ml BSA; Sigma)
with 0.5 nM of labeled chemokine in the presence of different
concentrations of unlabeled cytokines at 4°C for 2 h. At the end
of the incubation, cells were pelleted through a cushion of silicon oil
by microcentrifugation. The radioactivity present in the tip of the
tubes and in the supernatants was evaluated by using a gamma counter.
Flow cytometry analysis of MIP-1 binding to PMN was performed with
the Fluorokine staining kin (R&D Systems, Minneapolis, MN)
following the manufacturer’s recommendations. Fluorescence was
evaluated using a FACStar as described above.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows that PMN in resting
conditions express abundant levels of mRNA for CXCR1 and CXCR2, the two
IL-8 receptors, and for CXCR4, the SDF-1 receptor. As expected (18),
CXCR3, the receptor for IP-10 and Mig, was not expressed in PMN (data
not shown). Although human PMN do not respond to CC chemokines (2, 4, 5, 6), they express detectable levels of CCR1, the receptor for
MIP-1, RANTES, MCP-3, and MIP-5/HCC2 (14, 19, 20, 21), and, at a lower
level, CCR3, the receptor for eotaxin, RANTES, MCP-3, MCP-4, and
MIP-5/HCC2 (14, 22, 23). CCR2, the receptor for MCP-1, MCP-2, MCP-3,
and MCP-4 (24, 25), CCR4, the thymus and activation regulated chemokine
receptor (26), and CCR5, the receptor for MIP-1ß, MIP-1, and
RANTES (27, 28), were barely detectable under these experimental
conditions (Fig. 1). Incubation of PMN with an optimal concentration of
IFN- (500 U/ml; 25 ng/ml) for 4 h strongly increased the
expression of CCR1 and, at a lower level, of CCR3 as evaluated by
Northern blot analysis. The expression of CCR2, CCR4, and CCR5 was not
changed in IFN--treated PMN compared with control cells (Fig. 1).
Similarly, the expression of CXCR1, CXCR2, and CXCR4 was not increased
by IFN- treatment, and, in some donors, the treatment resulted in a
decrease of CXCR4 expression (Fig. 1).
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on CCR1 expression was concentration-dependent,
starting at 50 U/ml and becoming maximal at 500 U/ml IFN- with an
approximate 10-fold increase in the representative experiment shown in
Fig. 2, and with an average increase of
24 ± 8-fold over control (n = 8). Increased
expression of CCR1 was already detectable after 1-h incubation and
reached a plateau after 2-h stimulation (Fig. 3). Induction of CCR3 by IFN- showed a
similar dose response to CCR1 but was lower with an approximate 2-fold
increase in the representative experiments shown in Fig. 2, and with an
average increase of 3.5 ± 0.5-fold over control
(n = 5), and slower, becoming detectable after 4-h
stimulation (Fig. 3).
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selectively up-regulates the expression of
the CC chemokine receptors CCR1 and CCR3, it was important to
investigate the functional relevance of these increases. As expected,
freshly isolated PMN (data not shown) or PMN cultured at 37°C for
6 h respond to IL-8 and GRO- in a concentration-dependent
manner (Fig. 4 and data not shown).
Conversely, resting PMN do not migrate in response to the CC chemokines
MCP-1, MCP-3, MIP-1, MIP-1ß, RANTES, MIP-5/HCC2, and eotaxin (Fig. 4). However, PMN incubated in the presence of 500 U/ml IFN- for
6 h acquired the ability to respond in a concentration-dependent
manner to MCP-3, MIP-5/HCC2, MIP-1, RANTES, and eotaxin (Fig. 4).
Identical results were obtained with sorted CD16+ PMN (data
not shown). This result is in agreement with the observed increased
mRNA expression for CCR1 and CCR3 (Fig. 1
). Consistently, with Northern
blot analysis, IFN--treated PMN did not migrate to MCP-1 (CCR2) and
MIP-1ß (CCR5) (Fig. 4). PMN chemotactic response to GRO-, a ligand
for CXCR2, and to IL-8 were not changed in a reproducible manner by
IFN- (Fig. 4, and data not shown). Similarly, the agonists active in
chemotactic assays induced calcium transients in IFN--treated PMN
(data not shown). The effect of IFN- on chemotaxis and calcium was
time-dependent, reaching maximal induction after 6-h stimulation (data
not shown).
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on cell membrane receptor
expression, two different approaches were taken. First, binding studies
with [125I]MCP-3 were performed. Fig. 5A shows that PMN exposed to
500 U/ml IFN- for 6 h possess 4200 ± 1000 receptors per
cell with a Kd = 0.95 ± 0.5 nM. No
specific binding was observed in control PMN (not shown). In addition,
only IFN--treated PMN, but not control cells, specifically bound
biotinylated MIP-1, as evaluated by flow cytometry analysis (Fig. 5B). Second, chemotaxis of IFN--treated PMN was performed
in the presence of a specific blocking mAb (7B11) of CCR3 (29) or in
the presence of AOP-RANTES, a potent receptor antagonist (30). As shown
in Fig. 6A, chemotactic
response to eotaxin was strongly inhibited in the presence of 7B11
while migration to IL-8 was not affected. Similarly, chemotaxis of
IFN--treated PMN was inhibited in a concentration dependent manner
by AOP-RANTES. Again, IL-8 response was not affected by this receptor
antagonist (Fig. 6B). Altogether, these results indicate
that the effect of CC chemokines on IFN--treated PMN was mediated by
specific membrane receptors (i.e., CCR1 and CCR3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is able to up-regulate the
expression of CC chemokine receptors in PMN evaluated by Northern blot
and ligand binding analyses. The effect showed a certain degree of
selectivity since, among the receptors investigated (CXCR1–4 and
CCR1–5), CCR1 and CCR3 were the only ones found to be induced by
IFN-. The effect of IFN- was rapid (1 h),
concentration-dependent (EC50 70 U/ml and 50 U/ml for CCR1
and CCR3, respectively), and more pronounced for CCR1 than for CCR3
(24- and 3.5-fold increase, respectively). Preliminary results indicate
that, as for signals that affect chemokine receptor mRNA levels in
monocytes (12, 31), IFN- modulates the stability of CCR3 and CCR1
transcripts in PMN (R.B. and S.S., unpublished data). PMN exposed to
IFN- became responsive to a restricted panel of CC chemokines in
terms of chemotaxis and calcium fluxes. MIP-1, RANTES, MCP-3, and
MIP-5/HCC2 are known to bind CCR1. Eotaxin, in addition to
RANTES, MCP-3, and -4, binds to CCR3. Thus, the spectrum of active CC
chemokines entirely overlaps with the pattern of ligands for CCR1 and
CCR3. IFN--treated PMN were unresponsive to MCP-1 and to MIP-1ß,
in agreement with the lack of effect on CCR2 and CCR5 expression. These
data strongly suggest that the effect of IFN- is at the level of
receptor expression. However, it is possible that IFN- also acts as
a priming agent for chemokine-induced migration at steps downstream of
the receptor, as previously reported for other PMN functions (32).
CCR1 was cloned from a HL-60-neutrophil cDNA library, and it is known
to be expressed in PMN (19, 20). MIP-1, a ligand for CCR1, was
reported to activate a limited pattern of signaling events in human
PMN, such as calcium flux and shape change. However, it was inactive in
inducing acidification of intracellular pH, degranulation, actin
polymerization, and chemotaxis (33). MIP-1 and MIP-1ß were shown
to be chemokinetic/chemotactic for murine PMN (34, 35), and, in a
recent report, it was shown that human PMN express specific binding
sites and are activated by MCP-3 (36). However, we and others have been
unable to observe a chemotactic response of human PMN in response to
either MIP-1 and MCP-3 in vitro (33, 37, 38, and this study). The
finding that activated PMN up-regulate CCR1 suggests that the apparent
discrepancies present in literature may depend on the different state
of cell activation due to multiple isolation procedures or differences
in cell handling. In this respect, it is interesting to note that
MIP-1 was shown to induce in vivo PMN infiltration in the mouse (35, 39), and P-815 murine tumor cells transduced with MCP-3 form tumors
with a high degree of PMN infiltration (40).
This study shows that IFN- activated PMN express a functional CCR3
receptor. These results are unexpected since eotaxin has been so far
considered one of the most selective chemokines, being able to activate
only eosinophils and basophils (4, 6, 7). Thus, it is possible that in
a cytokine-driven inflammatory or immune response, local production of
eotaxin could target multiple leukocyte populations. In this context it
is interesting to note that IFN- induces the production of eotaxin
in endothelial cells (41).
IFN- is a cytokine produced by activated lymphocytes and NK cells
and is a potent modulator of T lymphocyte-mediated immune responses
(42). IFN- also has multiple effects on phagocytic cells. It is a
prototypic macrophage activator, and it was shown to prime PMN for the
activation of the respiratory burst and granule secretion by Con A,
FMLP, and PMA (43, 44). IFN- is known to induce the expression of
adhesion molecules, such as intracellular adhesion molecule-1, and to
up-regulate MHC class II molecules (42). IFN- also synergizes with
other factors in the induction of the chemokines IP-10 (CXC), MCP-1,
MCP-3, and RANTES (CC) in mononuclear phagocytes and endothelial cells.
However, IFN- can also function as a negative signal for chemokine
production, being able to inhibit LPS-induced production of IL-8 and
MIP-1 in PMN and/or monocytes and endothelial cells (5, 45). The
present data showing the induction of CCR1 and CCR3 add an additional
level of complexity in the key role played by IFN- in inflammation
and immunity.
T cell-dependent immune response can be polarized in Th1 and Th2
pathways based on the profile of cytokine secretion (3). The prototypic
cytokine produced by Th1 cells is IFN-, in addition to IL-12, IL-2,
and TNF. These cytokines promote a phagocyte-dependent host response.
On the other hand, Th2 cells produce IL-4, IL-5, IL-10, and IL-13 and
provide optimal help for humoral immune responses and mucosal immunity
through the induction of Ig isotype switching and eosinophil growth and
differentiation (3). Neutrophils produce IL-12, which is a key mediator
for Th1 response (3, 46), and there is evidence that neutrophils may
play a role in orienting immunity toward Th1 type of responses. It was
reported that PMN-released IL-12 induces a protective Th1 response to
Candida albicans infection in vivo. Further, exogenous IL-12
was effective in protecting neutropenic mice against the infection
(47). Hence, we speculate that IFN- may not only directly promote
Th1 differentiation but also reorient the functional significance of
Th2 effector chemokines by broadening their spectrum of action to
neutrophils, which, in turn, favor type 1 responses.
Regulation of chemokine receptors is emerging as an alternative
mechanism to control the level and the specificity of leukocyte
migration. IL-2-activated, but not resting, T lymphocytes and NK cells
migrate in response to MCP-1, MCP-2, and MCP-3 (9, 10). CXCR3 is
expressed only in IL-2-activated T lymphocytes, and IL-2 up-regulates
CCR6 expression (9, 48). In PMN, IL-8 receptors can be modulated by
G-CSF and LPS (11). In monocytes, inflammatory agonists, such as LPS
and IFN-, down-regulated CCR2 (12, 49). On the other hand, molecules
with anti-inflammatory activity, such as IL-10 (13) and
glucocorticoid hormones (A.M. and S.S., unpublished data), up-regulate
certain CC chemokine receptors. Reciprocally, at least certain
prototypic primary proinflammatory agents induce chemokine production
and inhibit receptor expression. Hence, an emerging paradigm indicates
that at least some pro- and anti-inflammatory molecules exert
reciprocal and opposing influences on chemokine agonist production and
receptor expression. IFN- can now be added to the list of agonists
that play this yin/yang interplay.
In conclusion, this study shows that IFN-, a prototypic Th1
cytokine, induces the expression of CCR1 and CCR3 in PMN. These results
indicate that in certain conditions CC chemokines can activate not only
mononuclear cells but also PMN. In addition, IFN--activated PMN, and
we find this true also for monocytes, can respond to eotaxin, an
agonist so far considered selective for eosinophils. The use of CCR3 as
fusion coreceptor for certain HIV virus strains (50, 51, 52) provides
speculation about an additional role of IFN- in HIV infection and
progression.
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Footnotes |
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2 Current address: Millennium Pharmaceuticals, Cambridge, MA, 02139.
3 Address correspondence and reprint requests to Dr. Silvano Sozzani, Istituto di Ricerche Farmacologiche "Mario Negri", via Eritrea 62, 20157 Milan, Italy. E-mail address:
4 Abbreviations used in this paper: PMN, polymorphonuclear leukocyte; G-CSF, granulocyte-CSF; MCP, macrophage-chemotactic protein; MIP, monocyte-inflammatory protein.
Received for publication April 27, 1998. Accepted for publication September 21, 1998.
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R. M. Phillips, V. E. L. Stubbs, M. R. Henson, T. J. Williams, J. E. Pease, and I. Sabroe Variations in Eosinophil Chemokine Responses: An Investigation of CCR1 and CCR3 Function, Expression in Atopy, and Identification of a Functional CCR1 Promoter J. Immunol., June 15, 2003; 170(12): 6190 - 6201. [Abstract] [Full Text] [PDF]
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J. R. Bleharski, V. Kiessler, C. Buonsanti, P. A. Sieling, S. Stenger, M. Colonna, and R. L. Modlin A Role for Triggering Receptor Expressed on Myeloid Cells-1 in Host Defense During the Early-Induced and Adaptive Phases of the Immune Response J. Immunol., April 1, 2003; 170(7): 3812 - 3818. [Abstract] [Full Text] [PDF]
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 X. Zeng, T. A. Moore, M. W. Newstead, R. Hernandez-Alcoceba, W. C. Tsai, and T. J. Standiford Intrapulmonary Expression of Macrophage Inflammatory Protein 1{alpha} (CCL3) Induces Neutrophil and NK Cell Accumulation and Stimulates Innate Immunity in Murine Bacterial Pneumonia Infect. Immun., March 1, 2003; 71(3): 1306 - 1315. [Abstract] [Full Text] [PDF]
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D. K. Bhalla, P. G. Reinhart, C. Bai, and S. K. Gupta Amelioration of Ozone-Induced Lung Injury by Anti-Tumor Necrosis Factor-{alpha} Toxicol. Sci., October 1, 2002; 69(2): 400 - 408. [Abstract] [Full Text] [PDF]
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A. Menzies-Gow, S. Ying, I. Sabroe, V. L. Stubbs, D. Soler, T. J. Williams, and A. B. Kay Eotaxin (CCL11) and Eotaxin-2 (CCL24) Induce Recruitment of Eosinophils, Basophils, Neutrophils, and Macrophages As Well As Features of Early- and Late-Phase Allergic Reactions Following Cutaneous Injection in Human Atopic and Nonatopic Volunteers J. Immunol., September 1, 2002; 169(5): 2712 - 2718. [Abstract] [Full Text] [PDF]
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H. Nagase, M. Miyamasu, M. Yamaguchi, M. Imanishi, N. H. Tsuno, K. Matsushima, K. Yamamoto, Y. Morita, and K. Hirai Cytokine-mediated regulation of CXCR4 expression in human neutrophils J. Leukoc. Biol., April 1, 2002; 71(4): 711 - 717. [Abstract] [Full Text] [PDF]
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L. Michalec, B. K. Choudhury, E. Postlethwait, J. S. Wild, R. Alam, M. Lett-Brown, and S. Sur CCL7 and CXCL10 Orchestrate Oxidative Stress-Induced Neutrophilic Lung Inflammation J. Immunol., January 15, 2002; 168(2): 846 - 852. [Abstract] [Full Text] [PDF]
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K. A. Kernacki, R. P Barrett, S. McClellan, and L. D. Hazlett MIP-1{alpha} regulates CD4+ T cell chemotaxis and indirectly enhances PMN persistence in Pseudomonas aeruginosa corneal infection J. Leukoc. Biol., December 1, 2001; 70(6): 911 - 919. [Abstract] [Full Text] [PDF]
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 S. W. Chensue Molecular Machinations: Chemokine Signals in Host-Pathogen Interactions Clin. Microbiol. Rev., October 1, 2001; 14(4): 821 - 835. [Abstract] [Full Text] [PDF]
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Y. Dulkys, C. Kluthe, T. Buschermohle, I. Barg, S. Kno{beta}, A. Kapp, A. E. I. Proudfoot, and J. Elsner IL-3 Induces Down-Regulation of CCR3 Protein and mRNA in Human Eosinophils J. Immunol., September 15, 2001; 167(6): 3443 - 3453. [Abstract] [Full Text] [PDF]
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U. Forssmann, H.-J. Magert, K. Adermann, S. E. Escher, and W.-G. Forssmann Hemofiltrate CC chemokines with unique biochemical properties: HCC-1/CCL14a and HCC-2/CCL15 J. Leukoc. Biol., September 1, 2001; 70(3): 357 - 366. [Abstract] [Full Text] [PDF]
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R. L. Robson, R. M. McLoughlin, J. Witowski, P. Loetscher, T. S. Wilkinson, S. A. Jones, and N. Topley Differential Regulation of Chemokine Production in Human Peritoneal Mesothelial Cells: IFN-{{gamma}} Controls Neutrophil Migration Across the Mesothelium In Vitro and In Vivo J. Immunol., July 15, 2001; 167(2): 1028 - 1038. [Abstract] [Full Text] [PDF]
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S. Yamashiro, H. Kamohara, J.-M. Wang, D. Yang, W.-H. Gong, and T. Yoshimura Phenotypic and functional change of cytokine-activated neutrophils: inflammatory neutrophils are heterogeneous and enhance adaptive immune responses J. Leukoc. Biol., May 1, 2001; 69(5): 698 - 704. [Abstract] [Full Text]
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N. J. Coates and S. R. McColl Production of Chemokines In Vivo in Response to Microbial Stimulation J. Immunol., April 15, 2001; 166(8): 5176 - 5182. [Abstract] [Full Text] [PDF]
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R.-F. Guo, A. B. Lentsch, R. L. Warner, M. Huber-Lang, J. V. Sarma, T. Hlaing, M. M. Shi, N. W. Lukacs, and P. A. Ward Regulatory Effects of Eotaxin on Acute Lung Inflammatory Injury J. Immunol., April 15, 2001; 166(8): 5208 - 5218. [Abstract] [Full Text] [PDF]
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S. S. Cheng, J. J. Lai, N. W. Lukacs, and S. L. Kunkel Granulocyte-Macrophage Colony Stimulating Factor Up-Regulates CCR1 in Human Neutrophils J. Immunol., January 15, 2001; 166(2): 1178 - 1184. [Abstract] [Full Text] [PDF]
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 S. Yamashiro, J.-M. Wang, D. Yang, W.-H. Gong, H. Kamohara, and T. Yoshimura Expression of CCR6 and CD83 by cytokine-activated human neutrophils Blood, December 1, 2000; 96(12): 3958 - 3963. [Abstract] [Full Text] [PDF]
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 Z.-Z. Pan, L. Parkyn, A. Ray, and P. Ray Inducible lung-specific expression of RANTES: preferential recruitment of neutrophils Am J Physiol Lung Cell Mol Physiol, October 1, 2000; 279(4): L658 - L666. [Abstract] [Full Text] [PDF]
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N. Zimmermann, B. L. Daugherty, J. L. Kavanaugh, F. Y. El-Awar, E. A. Moulton, and M. E. Rothenberg Analysis of the CC chemokine receptor 3 gene reveals a complex 5' exon organization, a functional role for untranslated exon 1, and a broadly active promoter with eosinophil-selective elements Blood, October 1, 2000; 96(7): 2346 - 2354. [Abstract] [Full Text] [PDF]
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A. P. Vicari, S. Ait-Yahia, K. Chemin, A. Mueller, A. Zlotnik, and C. Caux Antitumor Effects of the Mouse Chemokine 6Ckine/SLC Through Angiostatic and Immunological Mechanisms J. Immunol., August 15, 2000; 165(4): 1992 - 2000. [Abstract] [Full Text] [PDF]
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J. A. Belperio, M. D. Burdick, M. P. Keane, Y. Y. Xue, J. P. Lynch III, B. L. Daugherty, S. L. Kunkel, and R. M. Strieter The Role of the CC Chemokine, RANTES, in Acute Lung Allograft Rejection J. Immunol., July 1, 2000; 165(1): 461 - 472. [Abstract] [Full Text] [PDF]
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C. Murdoch and A. Finn Chemokine receptors and their role in inflammation and infectious diseases Blood, May 15, 2000; 95(10): 3032 - 3043. [Abstract] [Full Text] [PDF]
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R. Bonecchi, F. Facchetti, S. Dusi, W. Luini, D. Lissandrini, M. Simmelink, M. Locati, S. Bernasconi, P. Allavena, E. Brandt, et al. Induction of Functional IL-8 Receptors by IL-4 and IL-13 in Human Monocytes J. Immunol., April 1, 2000; 164(7): 3862 - 3869. [Abstract] [Full Text] [PDF]
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S. C. Lee, M. E. Brummet, S. Shahabuddin, T. G. Woodworth, S. N. Georas, K. M. Leiferman, S. C. Gilman, C. Stellato, R. P. Gladue, R. P. Schleimer, et al. Cutaneous Injection of Human Subjects with Macrophage Inflammatory Protein-1{alpha} Induces Significant Recruitment of Neutrophils and Monocytes J. Immunol., March 15, 2000; 164(6): 3392 - 3401. [Abstract] [Full Text] [PDF]
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 J. Elsner, M. Mack, H. Bruhl, Y. Dulkys, D. Kimmig, G. Simmons, P. R. Clapham, D. Schlondorff, A. Kapp, T. N. C. Wells, et al. Differential Activation of CC Chemokine Receptors by AOP-RANTES J. Biol. Chem., March 10, 2000; 275(11): 7787 - 7794. [Abstract] [Full Text] [PDF]
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A. E. I. Proudfoot, R. Buser, F. Borlat, S. Alouani, D. Soler, R. E. Offord, J.-M. Schroder, C. A. Power, and T. N. C. Wells Amino-terminally Modified RANTES Analogues Demonstrate Differential Effects on RANTES Receptors J. Biol. Chem., November 5, 1999; 274(45): 32478 - 32485. [Abstract] [Full Text] [PDF]
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