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The Journal of Immunology, 1999, 162: 474-479.
Copyright © 1999 by The American Association of Immunologists

Up-Regulation of CCR1 and CCR3 and Induction of Chemotaxis to CC Chemokines by IFN-{gamma} in Human Neutrophils1

Raffaella Bonecchi*, Nadia Polentarutti*, Walter Luini*, Alessandro Borsatti*, Sergio Bernasconi*, Massimo Locati*, Christine Power{dagger}, Amanda Proudfoot{dagger}, Timothy N. C. Wells{dagger}, Charles Mackay2,{ddagger}, Alberto Mantovani*,§ and Silvano Sozzani3,*

* Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy; {dagger} Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, Geneva, Switzerland; {ddagger} LeukoSite Inc., Cambridge, MA; and § Università di Brescia, Brescia, Italy


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Human neutrophils (polymorphonuclear leukocytes; PMN) respond to some CXC chemokines but do not migrate to CC chemokines. Recent work has shown that chemokine receptors can be modulated by inflammatory cytokines. In this study, the effect of IFN-{gamma}, a prototypic Th1 cytokine, on chemokine receptor expression in PMN was investigated. IFN-{gamma} 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-{gamma}-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{alpha}, RANTES, MCP-3, MIP-5/HCC2, and eotaxin. 7B11, a mAb for CCR3, inhibited the chemotactic response of IFN-{gamma}-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-{gamma} 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
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Leukocyte subsets are selectively accumulated during immune and inflammatory processes in response to the local production of inflammatory cytokines (1, 2). Both the cytokine profile and the cellular components present at the site of inflammation, in addition to the nature of the pathogen itself, are important factors for the induction of a polarized immune response (i.e., Th1 vs Th2 pathway) (3).

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 {alpha}) 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-{gamma}, a prototypic Th1 cytokine, on the expression of chemokine receptors in PMN.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cytokines

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{alpha} 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-{gamma} (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-{gamma} as specified in the text. Cell viability in control and IFN-{gamma}-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 [{alpha}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{alpha} 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.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Fig. 1Go 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{alpha}, 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{alpha}, and RANTES (27, 28), were barely detectable under these experimental conditions (Fig. 1Go). Incubation of PMN with an optimal concentration of IFN-{gamma} (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-{gamma}-treated PMN compared with control cells (Fig. 1Go). Similarly, the expression of CXCR1, CXCR2, and CXCR4 was not increased by IFN-{gamma} treatment, and, in some donors, the treatment resulted in a decrease of CXCR4 expression (Fig. 1Go).



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  		FIGURE 1. Effect of IFN-{gamma} on the expression of chemokine receptors in PMN. Total RNA (10 µg) was purified from PMN incubated for 4 h in the presence or absence of 500 U/ml of IFN-{gamma} and used in Northern blot analysis. Results are representative of at least three different cell preparations. The autoradiographies shown were obtained after 12 h of exposure. Ethidium bromide staining is reported below.

 
The effect of IFN-{gamma} on CCR1 expression was concentration-dependent, starting at 50 U/ml and becoming maximal at 500 U/ml IFN-{gamma} with an approximate 10-fold increase in the representative experiment shown in Fig. 2Go, 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. 3Go). Induction of CCR3 by IFN-{gamma} showed a similar dose response to CCR1 but was lower with an approximate 2-fold increase in the representative experiments shown in Fig. 2Go, and with an average increase of 3.5 ± 0.5-fold over control (n = 5), and slower, becoming detectable after 4-h stimulation (Fig. 3Go).



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  		FIGURE 2. Dose-response of IFN-{gamma} on CCR1, CCR3, and CXCR2 mRNA expression. PMN were stimulated with increasing concentrations of IFN-{gamma} for 6 h. Total RNA (10 µg) was purified and used in Northern blot analysis. Results of a single experiment representative of two are shown. A, Autoradiographies were obtained after 12 h of exposure. B, Densitometric analysis of the data.

 


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  		FIGURE 3. Time-course of CCR1 and CCR3 expression in IFN-{gamma}-stimulated PMN. Total RNA (10 µg) was purified from control or IFN-{gamma}-treated (500 U/ml) PMN and used in Northern blot analysis. Results are representative of two experiments. Autoradiographies were obtained after 12 h of exposure.

 
Having observed that IFN-{gamma} 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-{gamma} in a concentration-dependent manner (Fig. 4Go and data not shown). Conversely, resting PMN do not migrate in response to the CC chemokines MCP-1, MCP-3, MIP-1{alpha}, MIP-1ß, RANTES, MIP-5/HCC2, and eotaxin (Fig. 4Go). However, PMN incubated in the presence of 500 U/ml IFN-{gamma} for 6 h acquired the ability to respond in a concentration-dependent manner to MCP-3, MIP-5/HCC2, MIP-1{alpha}, RANTES, and eotaxin (Fig. 4Go). 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. 1Go). Consistently, with Northern blot analysis, IFN-{gamma}-treated PMN did not migrate to MCP-1 (CCR2) and MIP-1ß (CCR5) (Fig. 4Go). PMN chemotactic response to GRO-{gamma}, a ligand for CXCR2, and to IL-8 were not changed in a reproducible manner by IFN-{gamma} (Fig. 4Go, and data not shown). Similarly, the agonists active in chemotactic assays induced calcium transients in IFN-{gamma}-treated PMN (data not shown). The effect of IFN-{gamma} on chemotaxis and calcium was time-dependent, reaching maximal induction after 6-h stimulation (data not shown).



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  		FIGURE 4. Effect of IFN-{gamma} on chemotactic response of PMN to CC chemokines. PMN were incubated in presence or absence of 500 U/ml IFN-{gamma} for 6 h and then tested for their ability to migrate across a 5-µm pore-size polycarbonate filter in response to different concentrations of the indicated chemokines. At the end of the incubation (60 min), the number of cells in five high-power microscope-immersion fields was evaluated. Results of one experiment, representative of three independent experiments, are shown. Results are expressed as the percent of IL-8 response (115 ± 9% and 123 ± 7% for control and IFN-{gamma}-treated PMN, respectively). Basal migration against medium was 23 ± 3 and 35 ± 1 cells for control and IFN-{gamma}-treated PMN, respectively.

 
Finally, to investigate the effect of IFN-{gamma} on cell membrane receptor expression, two different approaches were taken. First, binding studies with [125I]MCP-3 were performed. Fig. 5GoA shows that PMN exposed to 500 U/ml IFN-{gamma} 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-{gamma}-treated PMN, but not control cells, specifically bound biotinylated MIP-1{alpha}, as evaluated by flow cytometry analysis (Fig. 5GoB). Second, chemotaxis of IFN-{gamma}-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. 6GoA, chemotactic response to eotaxin was strongly inhibited in the presence of 7B11 while migration to IL-8 was not affected. Similarly, chemotaxis of IFN-{gamma}-treated PMN was inhibited in a concentration dependent manner by AOP-RANTES. Again, IL-8 response was not affected by this receptor antagonist (Fig. 6GoB). Altogether, these results indicate that the effect of CC chemokines on IFN-{gamma}-treated PMN was mediated by specific membrane receptors (i.e., CCR1 and CCR3).



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  		FIGURE 5. Effect of IFN-{gamma} on chemokine surface receptor expression. PMN were incubated in the presence of 500 U/ml IFN-{gamma} for 6 h before being tested. A, Displacement of 125I-MCP-3 binding. Control and IFN-{gamma}-treated PMN were incubated with 0.5 nM labeled MCP-3 in the presence of increasing quantities of unlabeled cytokines. B, Flow cytometry assessment of biotinylated MIP-1{alpha}. The results show the percent of positive cells. Mononuclear leukocytes tested in parallel gave a 45% of MIP-1{alpha} binding.

 


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  		FIGURE 6. Inhibition of PMN chemotaxis by 7B11 mAb and AOP- RANTES. PMN incubated in presence of 500 U/ml IFN-{gamma} for 6 h were tested for their response to an optimal concentration (1 µg/ml) of eotaxin (A) or RANTES (B). IL-8 was used at 100 ng/ml as reference chemoattractant. Just before the assay, 7B11 and AOP-RANTES were added to the cells or mixed to the chemoattractant, respectively. Average results ± SD of one experiment representative of two experiments are shown. Results are expressed as the percent of response in the absence of addiction (104 ± 8%, 56 ± 4%, and 64 ± 3% for IL-8, eotaxin, and RANTES, respectively). Neither 7B11 nor AOP-RANTES modified basal (against medium) migration (data not shown).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study reports that IFN-{gamma} 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-{gamma}. The effect of IFN-{gamma} 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-{gamma} modulates the stability of CCR3 and CCR1 transcripts in PMN (R.B. and S.S., unpublished data). PMN exposed to IFN-{gamma} became responsive to a restricted panel of CC chemokines in terms of chemotaxis and calcium fluxes. MIP-1{alpha}, 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-{gamma}-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-{gamma} is at the level of receptor expression. However, it is possible that IFN-{gamma} 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{alpha}, 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{alpha} 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{alpha} 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{alpha} 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-{gamma} 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-{gamma} induces the production of eotaxin in endothelial cells (41).

IFN-{gamma} is a cytokine produced by activated lymphocytes and NK cells and is a potent modulator of T lymphocyte-mediated immune responses (42). IFN-{gamma} 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-{gamma} 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-{gamma} 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-{gamma} can also function as a negative signal for chemokine production, being able to inhibit LPS-induced production of IL-8 and MIP-1{alpha} 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-{gamma} 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-{gamma}, 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-{gamma} 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-{gamma}, 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-{gamma} can now be added to the list of agonists that play this yin/yang interplay.

In conclusion, this study shows that IFN-{gamma}, 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-{gamma}-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-{gamma} in HIV infection and progression.


   Footnotes
 
1 This work was supported by Istituto Superiore di Sanità (Project AIDS and Italy US Program on Cancer Research), by 40% fund from Ministero dell’Universitá e della Ricerca Scientifica e Technologica, Italy, and has been conducted in part under a research contract with Consorio Autoimmunità Tardiva, Pomezia, Italy, within the "Programma Nazionale Farmaci-seconda fase" of the Italian Ministry of the University of Scientific and Technological Research. The generous contribution of the Italian Association for Cancer Research (AIRC) is gratefully acknowledged. R.B. and A.B. are the recipients of a fellowship of Fondazione A. and A. Valenti and Alfredo Leonardi Fund and G. L. Pfeiffer Foundation, respectively. M. L. is a Fondazione Italiana per la Ricerca sul Cancro fellow. Back

2 Current address: Millennium Pharmaceuticals, Cambridge, MA, 02139. Back

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: Back

4 Abbreviations used in this paper: PMN, polymorphonuclear leukocyte; G-CSF, granulocyte-CSF; MCP, macrophage-chemotactic protein; MIP, monocyte-inflammatory protein. Back

Received for publication April 27, 1998. Accepted for publication September 21, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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