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CHEMOKINES
From the Department of Anatomy, Institute of
Basic Medical Sciences, University of Oslo, Norway, and Tanabe Research
Laboratories, San Diego, CA.
Using flow cytometric and RNase protection assays, this study
examined the expression of chemokine receptors in nonactivated natural
killer (NK) cells and compared this expression with NK cells activated
with interleukin (IL)-2, which either adhered to plastic flasks (AD) or
did not adhere (NA). None of the NK cell subsets expressed CXCR2,
CXCR5, or CCR5. The major differences between these cells include
increased expression of CXCR1, CCR1, CCR2, CCR4, CCR8, and
CX3CR1 in AD when compared to NA or nonactivated NK cells.
The chemotactic response to the CXC and CC chemokines correlated with
the receptor expression except that all 3 populations responded to
GRO- Natural killer (NK) cells were first discovered
because of the ability of a small population of blood lymphocytes (also
known as large granular lymphocytes, or LGL) to kill tumor cells
(reviewed in reference 1). Although it was difficult to isolate highly
purified NK cells based on the technologies available, Vujanovic et al successfully purified LGL from rat spleens.2 These cells
are generated by adherence to plastic flasks after activation with interleukin (IL)-2 and are designated as adherent lymphokine-activated killer (AD-LAK) cells. Because of their potential application in the
treatment of cancer patients, we examined their in vivo tissue
distribution and reported that these cells have restricted tissue
localization.3 Also, another population of killer cells was recovered from cells cultured with IL-2. These do not adhere to
plastic flasks and are designated as nonadherent lymphokine-activated killer (NA-LAK) cells. On examining their cytolytic behavior, the NA
cells show lower NK cell activity than the AD cells.4,5 Later work showed that AD cells accumulate at the sites of pulmonary and hepatic B16 melanoma in mice.6 In a more related work, Vujanovic et al7 showed that AD cells migrate
significantly better than NA cells into the spheroids of human squamous
cell carcinoma of the head and neck or breast carcinoma, emphasizing the antitumor therapeutic potential of adherent IL-2-activated NK
cells. Subsequent studies showed that AD cells in conjunction with IL-2
eliminate liver metastases in a xenogeneic tumor model, where nude mice
bear human gastric carcinoma.8,9 Also, it was observed
that some of these cells establish a cell-to-cell contact with
metastatic cells.6-9 However, the mechanisms contributing to the elimination of tumors, and to the close contact between adherent
cells and tumor cells, are to a large extent not known.
Most of the above studies were conducted before the surge of
chemokines. These low-molecular-weight molecules are divided into 4 subfamilies: CXC or Although these results are informative, they do not provide a uniform
source of identifying chemokine receptors on NK cells. In addition, the
effect of activating NK cells with IL-2 on the expression of chemokine
receptors has not been addressed in these studies. Here, we
systematically investigated the expression of chemokine receptors in
nonactivated NK cells and compared this expression with the expression
of these receptors in IL-2-activated (adherent "AD" versus
nonadherent "NA") cells. Nonactivated T cells are included because
the expression of chemokine receptors in these cells is well documented.
Culture medium and reagents
Preparation of NK and IL-2-activated NK cells
Chemotaxis assay Blind well chemotaxis chambers with a lower well volume of 200 µL were used. A maximum volume of 200 µL RPMI medium containing 1% bovine serum albumin was placed in the lower wells in the presence or absence of chemokines. Cells (4 × 105) were placed in the upper compartments of Boyden chambers above the filters. The chambers were incubated for 2 hours at 37°C in a 5% CO2 incubator. The filters were then removed, dehydrated, and stained with 15% Giemsa stain for 7 minutes and then mounted on glass slides. Cells in 10 high-power fields from 2 filters were counted and averaged for each sample. Migration index was calculated as the number of cells migrating toward the concentration gradient of chemokines divided by the number of cells migrating toward medium only.Flow cytometric analysis For the detection of CCR4 or CCR7, the cells were permeabilized before introduction of antibodies, which detect the carboxy terminal of these receptors, as recently described.20 For the detection of the other chemokine receptors, cells (1 × 106/mL) were incubated with 1 µg/mL monoclonal or polyclonal antichemokine receptors for 1 hour at 4°C, washed, and then incubated with 1:100 dilution of F(ab')2 fluorescein isothiocyanate (FITC)-conjugated rabbit antimouse for 45 minutes at 4°C, washed 3 times, and then examined. For CX3CR1, the secondary antibody was FITC-conjugated F(ab')2 goat antirabbit (Sigma). For CCR8, the secondary antibody was FITC-conjugated F(ab')2 rabbit antigoat. Regulation of chemokine receptor expression by cytokines or chemokines was determined by incubating nonactivated NK cells (1 × 106/mL) with culture medium, 15 µg/mL IFN- , or 20 ng/mL of TGF- 1, MIP-3,
SDF-1 , MDC, TARC, or I-309 for 5 days at 37°C. These concentrations have been found to be optimal for activating NK cells.20,22-24 The cells were washed and examined for the
presence of surface chemokine receptors, as described above.
Analysis of mRNA expression by multiprobe RPA Total RNA was prepared by guanidium thiocyanate/cesium chloride gradients following standard protocols. The specific mRNA for chemokine receptors was detected by the hCR5 and hCR6 multiprobe template sets (RiboQuant, Pharmingen, San Diego, CA), which contain templates for various chemokine receptors. Detection of mRNA for chemokines was done by using the hCK5 multiprobe template set (Pharmingen), which detects mRNA for various chemokines. In brief, antisense RNA probes were generated from DNA templates using T7 DNA-dependent RNA polymerase, in the presence of-32P]UTP (Amersham Pharmacia Biotech,
specific activity 10 µCi/µL). Labeled probes were hybridized with
total RNA (10 µg) overnight at 56°C. Unhybridized RNA was digested
with RNase according to Pharmingen's supplied procedures.
RNase-protected probes were resolved on denaturing 5% polyacrylamide
gel. The gels were dried and exposed to film (BIOMAX MS, Eastman Kodak,
Rochester, NY) at  70°C for 3 hours.
Radioligand binding assay The AD cells (3 × 105) were resuspended in a binding buffer containing 50 mM Hepes, 1 mM CaCl2, 5 mM MgCl2, 0.5% BSA, pH 7.0, and increasing concentrations of 125I-309 (specific activity 2000 Ci/mmol/L; Amersham Pharmacia Biotech, Buckinghamshire, UK) and cold I-309, in a final volume of 0.1 mL for 4 hours at room temperature with continuous shaking. In the competition for binding experiments, 100 pmol/L of 125I-309 and increasing concentrations of cold I-309, vMIP-I , or TARC were added to the cells in 0.1 mL. The cells were harvested into glass fiber filters using Skatron combi cell harvester (Skatron, Suffolk, UK), and washed with washing buffer containing 500 mM NaCl. After drying, scintillation fluids were added to the filters and counted in a Packard liquid scintillation analyzer. All assays were done in duplicate. Data were analyzed by nonlinear regression using Prism GraphPad (GraphPad Software, San Diego, CA).Statistical analysis Significant values were determined using the 2-tailed Student t test.
Analysis of CXC chemokine receptor expression in NK and IL-2-activated NK cells Figure 1 shows the expression of CXC chemokine receptors on nonactivated NK, AD, NA, and T cells. About 5% of AD and only 1% of nonactivated or NA cells expressed CXCR1, as determined by antibody to CXCR1. Using RPA, CXCR1 was shown in AD cells but not in other cell types (Figure 2). Using 2 different monoclonal antibodies, one shown here and the other from R&D Systems, none of the NK cell subsets expressed surface CXCR2. Only T cells (about 11%) expressed this receptor. The lack of expression of CXCR2 in nonactivated NK or IL-2-activated NK (AD and NA) cells is also shown in the RPA assay (Figure 2). CXCR3 was expressed on the surface of 21% AD, 9% NA, 5% to 12% nonactivated NK, and 39% T cells (Figure 1). The proportion of nonactivated T and NK cells expressing this receptor resembles those observed by Qin et al.16 The mRNA for CXCR3 was observed in these cells only after longer exposure of the gels (longer than 3 days; not shown).
Figure 1 also shows that CXCR4 was expressed on all cell types including nonactivated NK, NA, and AD NK cells (57%, 55%, and 18%, respectively). T cells highly expressed this receptor (94%). Messenger RNA for this receptor was also present in the 3 NK cell preparations (Figure 2). CXCR5 was reported to be expressed on B cells,25 and it binds the chemokine B-cell-attracting chemokine 1 (BCA-1), which is responsible for the migration of B cells into the B-cell areas in the spleen. Here, we observed that none of the NK cell preparations expressed this receptor (Figure 1). In contrast, about 25% of T cells expressed CXCR5. CX3CR1, the receptor for CX3C chemokine,15,26 is expressed on AD (16%) and T cells (27%), but not on nonactivated or NA NK cells (Figure 1). Similarly, mRNA for CX3CR1 was detected only in AD but not in nonactivated or NA NK cells (Figure 2). In contrast to our results, Imai et al15 showed mRNA, as well as receptor expression for CX3CR1, in nonactivated NK cells. The reason for these differences is not known, but it could be due to the process of preparing NK cells. In our hands, nonactivated NK cells were highly purified and contained more than 97% CD16+ cells. In addition, our method of negatively selecting NK cells ensured that they were not nonspecifically activated during the purification procedures. Effect of CXC chemokines on the chemotaxis of NK cells To correlate the expression of CXC and CX3C chemokine receptors with functional properties, we examined the effect of CXC and CX3C chemokines on the in vitro chemotaxis of the 3 different subsets of NK cells. Higher concentrations of IP-10 and fractalkine were used on nonactivated and NA cells than AD cells. Results in Figure 3A show that IL-8 was without effect. This is not surprising because IL-8 was previously found to be chemokinetic but not chemotactic for AD NK cells.13 IP-10 was chemoattractant for the 3 subsets (P < .003, < .005 and <. 0001, for nonactivated, NA, and AD, respectively, as compared to cells migrating in the absence of chemokines). Also SDF-1 was chemotactic for these cells
(P < .001, < .0001, and < .001). Although both
nonactivated and NA NK cells highly expressed CXCR4 (> 50% of the
cells were positive), the effect of this chemokine was more robust for
NA cells, suggesting that SDF-1 may have higher affinity for NA
cells than the other NK cell populations. Surprisingly, GRO- was
chemotactic for the 3 NK cell subsets (P < .0001),
although the receptor for this chemokine, CXCR2, was absent from these
cells. In addition, FK was chemotactic for nonactivated, NA, and AD
cells (P < .006, < .001, and < .0009, respectively),
although nonactivated and NA NK cells lacked the expression of
CX3CR1. To address the issue of the effect of GRO- and
fractalkine, we treated the 3 subsets with antibodies to CXCR2 or
CX3CR1. The cells (5 × 106/mL) were
pretreated with 0.1, 1, or 10 µg/mL of the antibodies for 1 hour at
4°C. Only results obtained with 10 µg/mL are shown. Figure 3B shows
that pretreatment of nonactivated, NA, or AD NK cells with mouse IgG or
monoclonal anti-CXCR2 did not affect their chemotaxis toward GRO-.
However, the same antibody inhibited more than 80% of GRO--induced
T-cell chemotaxis (data not shown). These results suggest that this
chemokine must use receptors other than CXCR2 to induce the chemotaxis
of NK cells. Similarly, pretreatment of nonactivated or NA NK cells
with rabbit IgG or rabbit anti-CX3CR1 did not affect their
chemotaxis toward fractalkine (Figure 3C). In contrast, pretreatment of
AD cells with rabbit anti-CX3CR1 inhibited their migration
toward fractalkine (P < .03 when compared to untreated
cells that migrate toward this chemokine). However, anti-CX3CR1 pretreated cells migrated significantly higher
than control cells (cells migrating in the absence of chemokine;
P < .005), indicating that anti-CX3CR1 does
not completely inhibit AD NK cell chemotaxis toward fractalkine.
Analysis of CC chemokine receptor expression in NK and IL-2-activated NK cells The expression of CC chemokine receptors examined in the flow cytometer is shown in Figure 4. Two different antibodies, one shown here and the other supplied by R&D Systems, did not detect surface expression of CCR1 (3% on NA, and < 0.5% on AD or nonactivated cells). In contrast, mRNA for this receptor was present in AD, and to a lower extent in NA or nonactivated cells (Figure 4). It is not clear why these cells did not show higher expression of surface CCR1. It is either that the protein is truncated or the antibody does not bind the epitopes expressed on the surface of these cells, although the same antibody stained CCR1 on the surface of T cells (Figure 4). Alternatively, because these cells secrete MIP-1
and RANTES, the ligands for this receptor (see below), these chemokines
may induce the internalization of CCR1. Hence, we were unable to detect
this receptor by flow cytometric analysis. It is worth noting that AD
cells respond to MIP-1 and RANTES,27 implicating that
IL-2-activated NK cells must express receptors for these chemokines,
which could be CCR1, because AD cells lack the expression of CCR5,
the other receptor for these chemokines.
The expression of CCR2 was higher on AD cells (8%), than on
nonactivated or NA NK cells (3% each). Also, mRNA for this receptor was present in AD cells (Figure 5). Naive
T cells did not express surface CCR2 (Figure 4). About 5% of AD NK
cells express CCR3, as compared to less than 1% on NA or nonactivated
NK cells (Figure 4). The mRNA for CCR3 was difficult to reveal in the
RPA assay (Figure 5). Expression of CCR4 was higher in AD cells (76%)
when compared to NA (22%) or nonactivated NK cells (14%). All 3 NK cell subsets expressed mRNA for CCR4. However, this expression was more
pronounced in AD cells than the other 2 cell populations (Figure 5).
Using 2 different anti-CCR5, one shown in Figure 4, and the other
obtained from R&D Systems (data not shown), we failed to detect any
surface CCR5 expression on the 3 subsets of NK cells. Using hCR5, mRNA
for this receptor was also absent in nonactivated, AD, and NA NK cells
(Figure 5). Bleul et al28 also noted that human
CD56+ NK cells do not express surface CCR5. The lack of
CCR5 expression supports our earlier findings showing that AD NK cells
do not respond to the concentration gradients of MIP-1 Surface CCR6 was expressed on AD (13%), as well as on nonactivated or NA NK cells (7% each), whereas about 29% of naive T cells expressed this receptor (Figure 4). The mRNA for CCR6 was present in the 3 NK cell subsets (Figure 2). CCR7 was expressed both on the surface (Figure 4) and at the mRNA level (Figure 2) in all 3 NK cell subsets examined. Interestingly, about 25% to 30% of AD cells expressed CCR8, which was lacking on either NA or nonactivated NK cells (< 0.5%). Heterogeneous naive T cells also lacked the expression of this receptor (Figure 4). In addition, only AD NK cells showed mRNA for this receptor (Figure 5). Effect of CC chemokines on the chemotaxis of NK cells To compare the expression of CC chemokine receptors with the ability of CC chemokines to induce the chemotaxis of these cells, we examined the chemotactic activity of the ligands for these receptors. Because CCR1 and CCR5 are not expressed on the surface of these cells, we did not examine the ligands for these receptors in the chemotaxis assay. Except for MIP-3, higher concentrations of chemokines were
used for nonactivated and NA cells than for AD cells. Results in Figure
6A show that MCP-1 induced the chemotaxis of nonactivated and NA cells (P < .01) and was a robust
chemoattractant for AD cells (P < .0001). Allavena et
al29 also observed that nonactivated NK cells respond to
MCP-1. Eotaxin, a CCR3 ligand, did not induce the chemotaxis of
nonactivated or NA cells, but was a chemoattractant for AD cells,
supporting the flow cytometric analysis data (Figure 4). MDC was
chemotactic for the 3 NK cell subsets (P < .002). This
correlates with the expression of CCR4 on the surface of these subsets
(Figure 4). MIP-3 and MIP-3 were also chemotactic for
nonactivated, NA, and AD NK cells (P < .002, < .001,
and < .0001 for MIP-3, and P < .0001 for MIP-3, respectively). Surprisingly, MIP-3 is not more potent than MIP-3, although CCR7 is highly expressed on the 3 NK cell subsets, when compared to the expression of CCR6 (Figure 4). The concentration of
MIP-3 (25 ng/mL) used to induce the chemotaxis of nonactivated and
NA cells was higher than that used for MIP-3 (1 ng/mL). Therefore, the difference in the response may be related to the affinity of these
chemokines for these cells. Others also observed that NK cells respond
to the ligands for CCR7.30
In contrast, only AD cells (P < .001, as compared to cells migrating in the absence of chemokine), but not nonactivated or NA NK cells responded to I-309 (Figure 6). These results confirm the RPA and the flow cytometric analysis results regarding the expression of CCR8 in AD cells only. To clearly establish the ability of AD cells to respond to CCR8 ligands, we examined the effect of vMIP-I, another ligand for CCR8.31,32 Our results show that as low as 10 pg/mL of vMIP-I induced the chemotaxis of AD cells (P < .002, as compared to cells migrating in the absence of chemokine). Also, 100, 1000 and 10 000 pg/mL concentrations of this chemokine were chemoattractants for AD cells (P < .001, < .002 and < .03, respectively, Figure 6B). Binding of radioligand I-309 to AD NK cells To further examine the presence of CCR8 on AD cells, we performed the radioligand-binding assay using 125I-309. Three different saturation binding experiments showed that I-309 binds to AD cells with a dissociation constant (Kd) of 213 ± 21 pmol/L (mean ± SE). This is higher than the affinity of this chemokine for Th2 cells,33 but is comparable to its affinity for IL-2-activated T cells.31 Next we investigated whether the binding of radiolabeled I-309 can be inhibited by chemokines reported to bind CCR8 transfectant cells.31,32,34 Results in Figure 6C show that cold I-309 and vMIP-I competed with the binding of 125I-309 to AD NK cells. The inhibitory concentration of 50% (IC50) for I-309 is 558 pmol/L, which is comparable to its Kd. Surprisingly, we observed that vMIP-I competed with higher affinity for CCR8 (IC50 is 123 pmol/L) than I-309. In addition TARC competed with I-309 for binding to AD NK cells with IC50 of 1640 pmol/L.Regulation of chemokine receptor expression on NK cells by various cytokines and chemokines The effect of various cytokines on the expression of chemokine receptors in NK cells has not been previously examined. It was reported that IL-2 up-regulates the expression of CCR2 in NK cells.35 However, NK cells are under the control of various cytokines and chemokines.1,24,36 Therefore, it was important to study whether proinflammatory and other regulatory cytokines such as TGF-1 and IFN- may influence the expression of
chemokine receptors in highly purified nonactivated NK cells. The
effect of constitutive chemokines (eg, MIP-3 and MDC) and
inflammatory chemokines (eg, TARC and I-309) on the expression of
various chemokine receptors in these cells was also examined. There was
no effect by these cytokines on the expression of chemokine receptors
24 hours after stimulation (data not shown). Except for a low induction of CCR1, none of the chemokines or cytokines affected the expression of
CCR2, CCR3, CCR5, CCR6, and CCR8 (because of the negative results, these data are not shown). Results of the expression of CXCR3 and CXCR4
are shown in Figure 7A, because these
receptors are the only ones that proved to be regulated by cytokines in
NK cells. We observed that NK cells acquired the expression of CXCR3
after in vitro incubation. Before culture, between 5% and 12% of NK cells expressed CXCR3, and this was increased to about 26% after culture (Figure 7A). The reason for this increase is unknown, but it
could be due to the effect of stress on the cells, removed from their
in vivo natural environment and placed in the in vitro cultures. This
increase was inhibited by IFN- and MIP-3, suggesting that under
these conditions, these factors control the expression of CXCR3. More
important, TGF-1 increased the expression of CXCR3. Similarly,
TGF-1 increased the level of CXCR4, when compared to the proportion
of cells incubated with medium only (Figure 7A). No effect with MDC,
TARC, or I-309 was observed on the expression of either CXCR3 or CXCR4.
Because TGF-1 does not induce the proliferation of NK
cells,24 the increase in the percentage of positive cells induced by TGF-1 must be due to an increase in the receptor level, rather than an increase in the number of cells expressing
these receptors.
To correlate the increase in the expression of CXCR3 and CXCR4 with the
response of these receptors to their ligands, we examined the
chemotactic response of NK cells incubated for 5 days with medium (CM)
or with various chemokines and cytokines, toward IP-10 (the ligand for
CXCR3) or SDF-1 Analysis of mRNA for chemokines in various subsets of NK cells Finally, we examined chemokine production by the various NK cell subsets. Figure 8 shows RPA analysis of the mRNA expression for various chemokines. All 3 NK cell subsets expressed mRNA for lymphotactin (Ltn), RANTES, MIP-1, and MIP-1
but not IP-10, MCP-1, IL-8, or I-309. This expression was similar in
IL-2-activated (AD and NA) and nonactivated NK cells. Although the
intensities of the chemokine bands in IL-2-activated cells were higher
than nonactivated cells, mRNA for the housekeeping L32 and GAPDH was also low in the nonactivated NK cells when compared to
IL-2-activated cells.
Natural killer cells and activated NK cells respond to various chemokines (reviewed in Maghazachi and Al-Aoukaty12) suggesting that they express receptors for these chemokines. Here, we examined the expression of chemokine receptors in nonactivated NK cells, as well as in IL-2 activated NK cells that either adhere to plastic flasks (adherent, AD) or those that do not adhere (nonadherent, NA). It was important to examine these cell types because of their differential tendency to migrate toward the sites of tumor growth. Except for the constitutive chemokine receptors, CXCR4 and CCR7, which
are expressed more in nonactivated or NA than in AD NK cells, all other
chemokine receptors that are detected are expressed higher in the AD
than in nonactivated or NA NK cells. These results indicate that NK
cells are not uniform in terms of their expression of chemokine
receptors and that this expression depends on their activation pattern.
The most important differences are: (1) increased surface expression
and mRNA for CXCR1, CCR4, CCR8 and CX3CR1, and (2)
increased mRNA for CCR1 after activation with IL-2,
specifically on NK cells that adhered to plastic flasks. Other receptors show this pattern: CXCR3
(AD > NA > nonactivated), CXCR4
(nonactivated = NA > AD), CCR2 (AD > NA = nonactivated), CCR3 (AD > NA = nonactivated), CCR6 (AD > NA = nonactivated), and CCR7 (nonactivated > AD > NA). All 3 subsets of NK cells lack the expression of CXCR2, CXCR5, and CCR5. Despite the low
expression of certain chemokine receptors on nonactivated or NA NK
cells, these cells migrate toward the respective chemokines, when these are used at high concentrations. For example, AD cells migrate toward
100 pg/mL of the inflammatory chemokine MCP-1, whereas 25 ng/mL induced
the migration of nonactivated and NA cells, although only 3% of
nonactivated and NA NK cells express CCR2. It is plausible that an
additional receptor may be expressed on the surface of NK cells that
facilitates the chemoattraction toward MCP-1. Similarly, higher
concentrations of IP-10, MDC, and MIP-3 Surprisingly, nonactivated and NA cells respond to fractalkine despite
their lack of CX3CR1 expression both at the protein and at
the transcriptional levels. This effect of fractalkine was not
inhibited by anti-CX3CR1, suggesting that fractalkine may
use another receptor in these cells to induce their chemotaxis. However, the same antibody inhibited the chemotactic response of AD NK
cells more than 50%, indicating that in these cells fractalkine uses 2 different receptors; one of them is CX3CR1. In addition, all 3 NK cell subsets respond to the CXC chemokine, GRO- Because CXCR3 is implicated in the recruitment of cytotoxic T
lymphocytes toward the sites of murine renal adenocarcinoma RENCA,37 we assumed that this might also be true for NK
cells. We have previously reported that the ligand for CXCR3, IP-10, induces the in vitro migration of AD cells.38 Also,
Mahalingam et al39 reported that the murine homologues of
IP-10, MuMig and Crg-2, recruit NK cells toward the sites of vaccinia
virus infection resulting in decreased infection with this virus.
TGF- The expression of CCR8 on AD cells supports our recent findings showing that these cells express this receptor.20 The importance of the current study is that this receptor is found to be exclusively expressed in AD but not in NA or nonactivated NK cells. Hence, a combination of IL-2 activation and adherence to plastic flasks results in the expression of this receptor, which is detected on about 25% to 30% of the AD cells 10 days after stimulation with IL-2. AD cells but not nonactivated or NA NK cells respond chemotactically to I-309, supporting the flow cytometric and RPA results. The etiologic agent of Kaposi sarcoma (KS), known as human herpes virus 8 (HH8), has been shown to encode at least 3 chemokines known as vMIP-I, vMIP-II, and vMIP-III.44 Using either CCR8 transfectants or IL-2-activated T cells, 2 groups observed that CCR8 is the receptor for vMIP-I.31,32 Our results show that vMIP-I is a potent chemoattractant for AD cells. In fact, it induces the chemotaxis of these cells at a much lower concentration than I-309. Competition for the binding of 125I-309 showed that vMIP-I has a higher affinity for AD cells than I-309. In addition, we observed that TARC competes efficiently with radiolabeled I-309 for binding AD cells. These results support those of others showing that TARC binds CCR8 in Jurkat cell line,34 and ours showing that TARC desensitizes the calcium flux response induced by I-309 in AD NK cells,20 but are in contrast to those reported in Th2 cells.33 The pattern of chemokine production by the various NK cell subsets is
the same. AD, NA, or nonactivated NK cells produce lymphotactin, RANTES, MIP-1
Submitted July 17, 2000; accepted September 21, 2000.
Supported by grants from the Norwegian Research Council, the Norwegian Cancer Society, and Anders Jahres Foundation. A.A.M. is a Senior Scientist of the Norwegian Cancer Society.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Azzam A. Maghazachi, Department of Anatomy, University of Oslo, POB 1105 Blindern, N-0317 Oslo, Norway; e-mail: azzam.maghazachi{at}basalmed.uio.no.
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  A. Durudas, J. M. Milush, H.-L. Chen, J. C. Engram, G. Silvestri, and D. L. Sodora Elevated Levels of Innate Immune Modulators in Lymph Nodes and Blood Are Associated with More-Rapid Disease Progression in Simian Immunodeficiency Virus-Infected Monkeys J. Virol., December 1, 2009; 83(23): 12229 - 12240. [Abstract] [Full Text] [PDF]
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S. M. Burke, T. B. Issekutz, K. Mohan, P. W. K. Lee, M. Shmulevitz, and J. S. Marshall Human mast cell activation with virus-associated stimuli leads to the selective chemotaxis of natural killer cells by a CXCL8-dependent mechanism Blood, June 15, 2008; 111(12): 5467 - 5476. [Abstract] [Full Text] [PDF]
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M. Hsu, S.-Y. Wu, S.-S. Chang, I.-J. Su, C.-H. Tsai, S.-J. Lai, A.-L. Shiau, K. Takada, and Y. Chang Epstein-Barr Virus Lytic Transactivator Zta Enhances Chemotactic Activity through Induction of Interleukin-8 in Nasopharyngeal Carcinoma Cells J. Virol., April 1, 2008; 82(7): 3679 - 3688. [Abstract] [Full Text] [PDF]
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C. Carlino, H. Stabile, S. Morrone, R. Bulla, A. Soriani, C. Agostinis, F. Bossi, C. Mocci, F. Sarazani, F. Tedesco, et al. Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy Blood, March 15, 2008; 111(6): 3108 - 3115. [Abstract] [Full Text] [PDF]
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B. B. Damaj, C. B. Becerra, H. J. Esber, Y. Wen, and A. A. Maghazachi Functional Expression of H4 Histamine Receptor in Human Natural Killer Cells, Monocytes, and Dendritic Cells J. Immunol., December 1, 2007; 179(11): 7907 - 7915. [Abstract] [Full Text] [PDF]
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S. Mizrahi, E. Yefenof, M. Gross, P. Attal, A. Ben Yaakov, D. Goldman-Wohl, B. Maly, N. Stern, G. Katz, R. Gazit, et al. A phenotypic and functional characterization of NK cells in adenoids J. Leukoc. Biol., November 1, 2007; 82(5): 1095 - 1105. [Abstract] [Full Text] [PDF]
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R. D. Berahovich, N. L. Lai, Z. Wei, L. L. Lanier, and T. J. Schall Evidence for NK Cell Subsets Based on Chemokine Receptor Expression J. Immunol., December 1, 2006; 177(11): 7833 - 7840. [Abstract] [Full Text] [PDF]
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D. Oz-Arslan, W. Ruscher, D. Myrtek, M. Ziemer, Y. Jin, B. B. Damaj, S. Sorichter, M. Idzko, J. Norgauer, and A. A. Maghazachi IL-6 and IL-8 release is mediated via multiple signaling pathways after stimulating dendritic cells with lysophospholipids J. Leukoc. Biol., August 1, 2006; 80(2): 287 - 297. [Abstract] [Full Text] [PDF]
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O. Wald, I. D. Weiss, H. Wald, H. Shoham, Y. Bar-Shavit, K. Beider, E. Galun, L. Weiss, L. Flaishon, I. Shachar, et al. IFN-{gamma} Acts on T Cells to Induce NK Cell Mobilization and Accumulation in Target Organs. J. Immunol., April 15, 2006; 176(8): 4716 - 4729. [Abstract] [Full Text] [PDF]
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L. M. Ebert, S. Meuter, and B. Moser Homing and Function of Human Skin {gamma}{delta} T Cells and NK Cells: Relevance for Tumor Surveillance J. Immunol., April 1, 2006; 176(7): 4331 - 4336. [Abstract] [Full Text] [PDF]
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J. Hanna, H. Mussaffi, G. Steuer, S. Hanna, M. Deeb, H. Blau, T. I. Arnon, N. Weizman, and O. Mandelboim Functional aberrant expression of CCR2 receptor on chronically activated NK cells in patients with TAP-2 deficiency Blood, November 15, 2005; 106(10): 3465 - 3473. [Abstract] [Full Text] [PDF]
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A. Kouroumalis, R. J. Nibbs, H. Aptel, K. L. Wright, G. Kolios, and S. G. Ward The Chemokines CXCL9, CXCL10, and CXCL11 Differentially Stimulate G{alpha}i-Independent Signaling and Actin Responses in Human Intestinal Myofibroblasts J. Immunol., October 15, 2005; 175(8): 5403 - 5411. [Abstract] [Full Text] [PDF]
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T. Walzer, M. Dalod, S. H. Robbins, L. Zitvogel, and E. Vivier Natural-killer cells and dendritic cells: "l'union fait la force" Blood, October 1, 2005; 106(7): 2252 - 2258. [Abstract] [Full Text] [PDF]
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T. S. Kim and S. Perlman Viral Expression of CCL2 Is Sufficient To Induce Demyelination in RAG1-/- Mice Infected with a Neurotropic Coronavirus J. Virol., June 1, 2005; 79(11): 7113 - 7120. [Abstract] [Full Text] [PDF]
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E. Merck, B. de Saint-Vis, M. Scuiller, C. Gaillard, C. Caux, G. Trinchieri, and E. E. M. Bates Fc receptor {gamma}-chain activation via hOSCAR induces survival and maturation of dendritic cells and modulates Toll-like receptor responses Blood, May 1, 2005; 105(9): 3623 - 3632. [Abstract] [Full Text] [PDF]
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D. N. Forthal, G. Landucci, T. B. Phan, and J. Becerra Interactions between Natural Killer Cells and Antibody Fc Result in Enhanced Antibody Neutralization of Human Immunodeficiency Virus Type 1 J. Virol., February 15, 2005; 79(4): 2042 - 2049. [Abstract] [Full Text] [PDF]
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C. L. Sentman, S. K. Meadows, C. R. Wira, and M. Eriksson Recruitment of Uterine NK Cells: Induction of CXC Chemokine Ligands 10 and 11 in Human Endometrium by Estradiol and Progesterone J. Immunol., December 1, 2004; 173(11): 6760 - 6766. [Abstract] [Full Text] [PDF]
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H. Takata, H. Tomiyama, M. Fujiwara, N. Kobayashi, and M. Takiguchi Cutting Edge: Expression of Chemokine Receptor CXCR1 on Human Effector CD8+ T Cells J. Immunol., August 15, 2004; 173(4): 2231 - 2235. [Abstract] [Full Text] [PDF]
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V. Veckman, M. Miettinen, J. Pirhonen, J. Siren, S. Matikainen, and I. Julkunen Streptococcus pyogenes and Lactobacillus rhamnosus differentially induce maturation and production of Th1-type cytokines and chemokines in human monocyte-derived dendritic cells J. Leukoc. Biol., May 1, 2004; 75(5): 764 - 771. [Abstract] [Full Text] [PDF]
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G. C. Hildebrandt, U. A. Duffner, K. M. Olkiewicz, L. A. Corrion, N. E. Willmarth, D. L. Williams, S. G. Clouthier, C. M. Hogaboam, P. R. Reddy, B. B. Moore, et al. A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation Blood, March 15, 2004; 103(6): 2417 - 2426. [Abstract] [Full Text] [PDF]
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B. G. Dorner, H. R.C. Smith, A. R. French, S. Kim, J. Poursine-Laurent, D. L. Beckman, J. T. Pingel, R. A. Kroczek, and W. M. Yokoyama Coordinate Expression of Cytokines and Chemokines by NK Cells during Murine Cytomegalovirus Infection J. Immunol., March 1, 2004; 172(5): 3119 - 3131. [Abstract] [Full Text] [PDF]
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A. Schafer, C. Schulz, M. Eigenthaler, D. Fraccarollo, A. Kobsar, M. Gawaz, G. Ertl, U. Walter, and J. Bauersachs Novel role of the membrane-bound chemokine fractalkine in platelet activation and adhesion Blood, January 15, 2004; 103(2): 407 - 412. [Abstract] [Full Text] [PDF]
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L. Stievano, V. Tosello, N. Marcato, A. Rosato, A. Sebelin, L. Chieco-Bianchi, and A. Amadori CD8+{alpha}{beta}+ T Cells That Lack Surface CD5 Antigen Expression Are a Major Lymphotactin (XCL1) Source in Peripheral Blood Lymphocytes J. Immunol., November 1, 2003; 171(9): 4528 - 4538. [Abstract] [Full Text] [PDF]
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M. Inngjerdingen, B. Rolstad, and J. C. Ryan Activating and Inhibitory Ly49 Receptors Modulate NK Cell Chemotaxis to CXC Chemokine Ligand (CXCL) 10 and CXCL12 J. Immunol., September 15, 2003; 171(6): 2889 - 2895. [Abstract] [Full Text] [PDF]
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K. Beider, A. Nagler, O. Wald, S. Franitza, M. Dagan-Berger, H. Wald, H. Giladi, S. Brocke, J. Hanna, O. Mandelboim, et al. Involvement of CXCR4 and IL-2 in the homing and retention of human NK and NK T cells to the bone marrow and spleen of NOD/SCID mice Blood, September 15, 2003; 102(6): 1951 - 1958. [Abstract] [Full Text] [PDF]
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V. Veckman, M. Miettinen, S. Matikainen, R. Lande, E. Giacomini, E. M. Coccia, and I. Julkunen Lactobacilli and streptococci induce inflammatory chemokine production in human macrophages that stimulates Th1 cell chemotaxis J. Leukoc. Biol., September 1, 2003; 74(3): 395 - 402. [Abstract] [Full Text] [PDF]
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S. Y. Thomas, R. Hou, J. E. Boyson, T. K. Means, C. Hess, D. P. Olson, J. L. Strominger, M. B. Brenner, J. E. Gumperz, S. B. Wilson, et al. CD1d-Restricted NKT Cells Express a Chemokine Receptor Profile Indicative of Th1-Type Inflammatory Homing Cells J. Immunol., September 1, 2003; 171(5): 2571 - 2580. [Abstract] [Full Text] [PDF]
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J. Hanna, O. Wald, D. Goldman-Wohl, D. Prus, G. Markel, R. Gazit, G. Katz, R. Haimov-Kochman, N. Fujii, S. Yagel, et al. CXCL12 expression by invasive trophoblasts induces the specific migration of CD16- human natural killer cells Blood, September 1, 2003; 102(5): 1569 - 1577. [Abstract] [Full Text] [PDF]
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A. Gismondi, J. Jacobelli, R. Strippoli, F. Mainiero, A. Soriani, L. Cifaldi, M. Piccoli, L. Frati, and A. Santoni Proline-Rich Tyrosine Kinase 2 and Rac Activation by Chemokine and Integrin Receptors Controls NK Cell Transendothelial Migration J. Immunol., March 15, 2003; 170(6): 3065 - 3073. [Abstract] [Full Text] [PDF]
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C. Trebst, S. M. Staugaitis, P. Kivisakk, D. Mahad, M. K. Cathcart, B. Tucky, T. Wei, M. R. S. Rani, R. Horuk, K. D. Aldape, et al. CC Chemokine Receptor 8 in the Central Nervous System Is Associated with Phagocytic Macrophages Am. J. Pathol., February 1, 2003; 162(2): 427 - 438. [Abstract] [Full Text] [PDF]
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M. S. Thomas, S. L. Kunkel, and N. W. Lukacs Differential Role of IFN-{gamma}-Inducible Protein 10 kDa in a Cockroach Antigen-Induced Model of Allergic Airway Hyperreactivity: Systemic Versus Local Effects J. Immunol., December 15, 2002; 169(12): 7045 - 7053. [Abstract] [Full Text] [PDF]
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K. Dunussi-Joannopoulos, K. Zuberek, K. Runyon, R. G. Hawley, A. Wong, J. Erickson, S. Herrmann, and J. P. Leonard Efficacious immunomodulatory activity of the chemokine stromal cell-derived factor 1 (SDF-1): local secretion of SDF-1 at the tumor site serves as T-cell chemoattractant and mediates T-cell-dependent antitumor responses Blood, August 13, 2002; 100(5): 1551 - 1558. [Abstract] [Full Text] [PDF]
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D. L. Hodge, W. B. Schill, J. M. Wang, I. Blanca, D. A. Reynolds, J. R. Ortaldo, and H. A. Young IL-2 and IL-12 Alter NK Cell Responsiveness to IFN-{gamma}-Inducible Protein 10 by Down-Regulating CXCR3 Expression J. Immunol., June 15, 2002; 168(12): 6090 - 6098. [Abstract] [Full Text] [PDF]
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M. T. Borchers, T. Ansay, R. DeSalle, B. L. Daugherty, H. Shen, M. Metzger, N. A. Lee, and J. J. Lee In vitro assessment of chemokine receptor-ligand interactions mediating mouse eosinophil migration J. Leukoc. Biol., June 1, 2002; 71(6): 1033 - 1041. [Abstract] [Full Text] [PDF]
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M. Inngjerdingen, K. M. Torgersen, and A. A. Maghazachi Lck is required for stromal cell-derived factor 1alpha (CXCL12)-induced lymphoid cell chemotaxis Blood, May 29, 2002; 99(12): 4318 - 4325. [Abstract] [Full Text] [PDF]
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A. Glatzel, D. Wesch, F. Schiemann, E. Brandt, O. Janssen, and D. Kabelitz Patterns of Chemokine Receptor Expression on Peripheral Blood {gamma}{delta} T Lymphocytes: Strong Expression of CCR5 Is a Selective Feature of V{delta}2/V{gamma}9 {gamma}{delta} T Cells J. Immunol., May 15, 2002; 168(10): 4920 - 4929. [Abstract] [Full Text] [PDF]
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M. J. Robertson Role of chemokines in the biology of natural killer cells J. Leukoc. Biol., February 1, 2002; 71(2): 173 - 183. [Abstract] [Full Text] [PDF]
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 K. Kakimi, T. E. Lane, S. Wieland, V. C. Asensio, I. L. Campbell, F. V. Chisari, and L. G. Guidotti Blocking Chemokine Responsive to {gamma}-2/Interferon (IFN)-{gamma} Inducible Protein and Monokine Induced by IFN-{gamma} Activity In Vivo Reduces the Pathogenetic but not the Antiviral Potential of Hepatitis B Virus-specific Cytotoxic T Lymphocytes J. Exp. Med., December 17, 2001; 194(12): 1755 - 1766. [Abstract] [Full Text] [PDF]
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K. Kakimi, T. E. Lane, F. V. Chisari, and L. G. Guidotti Cutting Edge: Inhibition of Hepatitis B Virus Replication by Activated NK T Cells Does Not Require Inflammatory Cell Recruitment to the Liver J. Immunol., December 15, 2001; 167(12): 6701 - 6705. [Abstract] [Full Text] [PDF]
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W. W. Hancock, W. Gao, V. Csizmadia, K. L. Faia, N. Shemmeri, and A. D. Luster Donor-Derived Ip-10 Initiates Development of Acute Allograft Rejection J. Exp. Med., April 16, 2001; 193(8): 975 - 980. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
(reviewed in reference 10). Also several chemokine receptors
including CXCR1 to CXCR5, CCR1 to CCR10, XCR1, and CX3CR1
have been cloned. Another classification based on function and stage of
maturation or activation was developed by Sallusto et
al.
constitutive and inflammatory. Recent
results showed that NK or IL-2-activated NK cells can be attracted in
vitro toward the concentration gradients of various chemokines
(reviewed in reference 12). Also, we reported that the CXC chemokine
IL-8 influences the chemokinesis of these cells.
5 M 2-ME (Sigma Chemical, St Louis, MO).
Monoclonal antibodies to CCR1, CCR2, CCR3, CCR5, CCR6, CXCR1, CXCR2,
CXCR3, CXCR4, and CXCR5 were obtained from Celltek Biotechnologies (Cap
Rouge, Quebec, Canada). Polyclonal antibodies to the carboxy terminal
of CCR4 and CCR7 were purchased from Research Diagnostics (Flanders,
NJ). Rabbit antibody to CX3CR1 was purchased from Terrey
Pines Biolabs (San Diego, CA). Affinity-purified goat antihuman CCR8
was purchased from Alexis Biochemicals (Laufelfingen, Switzerland).
Interferon (IFN)-
] and NA [
] and
100 pg/mL for AD [
] cells), Eotaxin (10 ng/mL for nonactivated and
NA and 1 ng/mL for AD cells), MDC (10 ng/mL for nonactivated and NA and
1 ng/mL for AD cells), MIP-3
; 10 pg/mL, 
; 10 000 pg/mL, 
) of
vMIP-I were examined. Migration index was calculated as the number of
cells migrating in the presence of chemokines divided by the number of
cells migrating in the presence of medium only (controls, shown in
white columns). Mean ± SD of 6 to 9 experiments. Panel C shows
competition binding analysis of 100 pmol/L 125I-309 to AD
cells, by cold I-309, TARC, or vMIP-I. Log concentrations of these
chemokines are shown in the X-axis, whereas the total count of binding
is shown in the Y-axis. IC50 for cold ligands is
also shown.
