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CHEMOKINES
From the Laboratories of Molecular Immunology,
Experimental Chemotherapy, and Immunobiology, Rega Institute for
Medical Research, and Department of Ophthalmology, Catholic University
of Leuven, Belgium; IRIBHN and Euroscreen SA, Université Libre de
Bruxelles, Belgium; and Laboratory of Clinical Biochemistry,
University of Antwerp, Wilrijk, Belgium.
The interferon (IFN)-inducible chemokines, specifically,
IFN- Chemokines constitute a family of low molecular
mass proteins that regulate the directed migration of specific
subclasses of leukocytes during normal and inflammatory
processes.1-3 The cellular specificity of chemokines is
determined by the restricted expression of chemokine receptors on
various leukocyte cell types.4 Chemokines are divided into
subfamilies depending on the position of the first 2 cysteines in their
primary sequence. The CC subfamily, with 2 adjacent cysteines, contains
more than 20 different proteins that regulate the migration of
monocytes, eosinophils, basophils, B and T lymphocytes, natural killer
(NK) cells, and dendritic cells. The CXC chemokine subfamily, with 2 cysteines separated by one other amino acid, contains several proteins
with a Glu-Leu-Arg (ELR) motif in front of the first cysteine. These
ELRCXC chemokines all attract neutrophilic granulocytes to sites of
inflammation. The CXC chemokines without an ELR motif can attract
monocytes and B or T lymphocytes. Three of the known non-ELRCXC
chemokines, specifically, interferon- The NH2-terminal region of most chemokines is crucial for
receptor binding and signaling activities. Some chemokines become chemotactic only when processed at the NH2-terminus, for
example, truncation of platelet basic protein (PBP) into NAP-2
(CXCL7).21 Others, for example, the monocyte chemotactic
proteins MCP-1 (CCL2), MCP-2 (CCL8), and MCP-3 (CCL7), lose their
chemotactic activity when NH2-terminal amino acids are
cleaved off.22,23 Aminopeptidases or endopeptidases that
process chemokines at the NH2-terminus play an important
role in the up-regulation or down-regulation of chemokine activities.
One of these enzymes, the membrane-associated protease dipeptidyl
peptidase IV (DPP IV, EC3.4.14.5) is highly specific. It cleaves off
dipeptides from polypeptides with a proline, alanine, or hydroxyproline
at the second position. DPP IV, which is expressed on fibroblasts and
epithelial and endothelial cells, is identical to the lymphocyte
surface glycoprotein and T-cell activation marker CD26.24
The extracellular domain of CD26/DPP IV also exists as a soluble and
proteolytically active form in plasma and in cerebrospinal and seminal
fluids. CD26/DPP IV interacts with CD45 (a protein tyrosine
phosphatase) and with adenosine deaminase, has costimulatory activity
in T-cell immune responses, plays a role in immune processes such as
allograft rejection, suppresses malignant transformation, and has been
implicated in the regulation of insulin secretion.24,25
Recently, CD26/DPP IV was found to cleave a number of chemokines, but
not cytokines.26 For example, removal by CD26/DPP IV of
the 2 NH2-terminal amino acids from stromal cell-derived
factor-1 (SDF-1 or CXCL12) resulted in significantly reduced
chemotactic and calcium-signaling activity due to a decreased affinity
for CXC chemokine receptor 4 (CXCR4).27,28 Accordingly,
SDF-1(3-68) processed by CD26/DPP IV lacks antiviral activity against
T-tropic human immunodeficiency virus type 1 (HIV-1) strains.
CD26 is highly expressed on Th1 cells and its expression is
up-regulated by IFN- Reagents and cell lines
In vitro truncation of chemokines by CD26/DPP IV
To determine the time course of the NH2-terminal
truncation, IP-10, Mig, and I-TAC (5 µM) were incubated with soluble
CD26/DPP IV (250, 25, 2.5, and 0.25 U/L) in 15 µL 50 mM Tris buffer,
pH 7.5, supplemented with 1 mM EDTA. The specificity of the reaction was checked by incubating the chemokines with Tris buffer alone. Samples (5 µL) were withdrawn after 5, 15, and 30 minutes, and the
reaction was stopped by addition of trifluoroacetic acid (final concentration of 0.1%). The samples were desalted on a C18 ZipTip (Millipore, Bedford, MA) and the relative amounts of the
NH2-terminally truncated chemokines were determined by ion
trap mass spectrometry. The time course of the truncation (shown in
Figure 1) was constructed by normalizing the incubation times,
taking into account that 25 U/L is close to the normal serum
concentration of DPP IV.32
Chemotaxis assays Peripheral blood mononuclear cells were purified from buffy coats from healthy volunteers as previously described.33 Mononuclear cells were stimulated with anti-CD3 antibodies (OKT3: ATCC CRL-8001) in RPMI 1640 (Biowhittaker Europe) with 10% FBS for 2 days before use. Alternatively, mononuclear cells were cultured in RPMI 1640 with 10% FBS and treated with phytohemagglutinin (PHA; 2 µg/mL) for 3 days, washed with RPMI 1640, and kept in culture for 2 to 3 weeks in RPMI 1640 supplemented with 10% FBS and 50 U/mL IL-2 before use in the chemotaxis assay.7Lymphocyte chemotaxis was performed in Boyden microchambers (Neuro Probe, Cabin John, MD) with fibronectin-coated, polyvinylpyrrolidone-free polycarbonate membranes (5-µm pore size, Corning Separations Division, Acton, MA). Lymphocytes were suspended in Hanks balanced salt solution (HBSS) plus 0.1% (wt/vol) human serum albumin (HSA) at 2 × 106 cells/mL and were allowed to migrate for 2 hours at 37°C. Before chemotaxis, CXCR3-transfected CHO cells were resuspended in HBSS plus 0.1% HSA and diluted to 1.5 × 106 cells/mL. Boyden chamber chemotaxis experiments were performed for 2 hours at 37°C with 8-µm pore size polyvinylpyrrolidone-free polycarbonate membranes. To study antagonism, truncated chemokines were added at inactive concentrations together with the active substance to the bottom well of the Boyden chambers. Cells that migrated through the membrane were stained with DiffQuick (Merck, Darmstadt, Germany) and counted microscopically in 10 oil immersion fields (× 500 magnification). The chemotactic index was calculated as the number of cells migrated to the sample divided by the number of cells spontaneously migrated to the sample dilution medium (HBSS + 0.1% HSA). Calcium-signaling and receptor-binding assays Alterations in intracellular calcium concentration ([Ca++]i) in response to chemokines were monitored by fluorescence spectrometry. Briefly, CXCR3-transfected cells were loaded with the fluorescent dye Fura-2-AM for 30 minutes at room temperature as previously described.31 Cells were washed with buffer containing 125 µM probenecid (ICN Biomedicals, Costa Mesa, CA), kept at 4°C, and preincubated for 10 minutes at 31°C before use. [Ca++]i were measured in an LS50B spectrofluorimeter (PerkinElmer) at a final cell concentration of 106 cells/mL in buffer containing 125 µM probenecid. During desensitization experiments, CD26/DPP IV-truncated CXCR3-ligands were first added at inactive concentrations followed by intact CXCR3 ligands. The increase in [Ca++]i after desensitization with the truncated chemokines was compared with the increase in [Ca++]i after the addition of an equal amount of dilution buffer to calculate the percentage desensitization.Competition for 125I-labeled I-TAC binding was measured on freshly isolated peripheral blood mononuclear cells or on CXCR3-transfected cells as described.34 Briefly, 2 × 106 cells were incubated for 2 hours at 4°C with 0.06 nM 125I I-TAC (Amersham Pharmacia Biotech, Uppsala, Sweden) and varying concentrations of unlabeled chemokine. Cells were centrifuged and washed 3 times with 2 mL phosphate-buffered saline (PBS) supplemented with 2% (wt/vol) bovine serum albumin (BSA) and the radioactivity present on the cells was measured in a gamma counter. In vivo test for antiangiogenic activity of chemokines Chemokines were tested for their angiogenic or angiostatic activity in the rabbit cornea micropocket model.16 Briefly, 32 mg sucralfate (Merck) was dissolved in 72 µL PBS. Then, 4 µL of this sucralfate solution was mixed with 4 µL Hydron solution (12% Hydron in ethanol; Interferon Sciences, New Brunswick, NJ) and 5-µL pellets were allowed to dry under UV light for 20 minutes. Subsequently, different concentrations of chemokines or dilution buffer (negative control) were dried on the pellets. One pellet was implanted 1 mm from the limbus into a corneal micropocket of each eye of an anesthetized New Zealand white rabbit. Neovascularization of the cornea was scored daily from day 4 to day 8 after implantation of the pellet. Maximal neovascularization was obtained between days 5 and 7. This maximal neovascularization was used for comparison.
Processing of CXCR3 ligands by CD26/DPP IV The NH2-terminal sequence analysis on commercially available recombinant IP-10 from various companies revealed that most proteins contained an extra methionine at the NH2-terminus (Met-IP-10). Automated Edman degradation on Mig and I-TAC (derived from PeproTech or R&D Systems), and on IP-10 from a batch without NH2-terminal methionine (PeproTech), confirmed the correct NH2-terminus for these recombinant chemokines (Table 1). Incubation of IP-10, I-TAC, and Mig with CD26/DPP IV resulted in the effective removal (> 95%) of the NH2-terminal dipeptide. After 18 hours of incubation with CD26/DPP IV, no remaining intact chemokine was detectable by Edman degradation. Proteolysis beyond the penultimate proline or proteolysis of Met-IP-10 was not observed, confirming the purity and specificity of CD26/DPP IV. For biologic evaluation, proteolytically cleaved CXCR3 ligands were purified by C8 RP-HPLC. The purity and Mr of the cleaved chemokines were confirmed by mass spectrometry, which excludes carboxy-terminal or internal processing (Table 1).
Mass spectrometry was used to study the time course of chemokine processing (Figure 1). When 5 µM IP-10 was incubated with serum concentrations (25 U/L) of CD26/DPP IV, 50% of the chemokine was truncated within the first 5 minutes and after 20 minutes less than 10% of the IP-10 proteins remained intact. In contrast, the kinetics of Mig processing were about 4 times slower (50% conversion in 20 minutes) than that of IP-10, whereas 50% and 90% of intact I-TAC was converted into I-TAC(3-73) within 1.5 and 6 minutes, respectively. Thus, CD26/DPP IV processed I-TAC more than 10-fold faster than Mig. Impaired lymphocyte chemotactic activity of IP-10 after CD26/DPP IV cleavage The chemotactic activity of Met-IP-10 and intact and CD26/DPP IV-truncated IP-10 was compared on activated (by PHA or anti-CD3) lymphocytes. A dose-dependent chemotactic effect was obtained with intact IP-10 from 1 nM onward on PHA-stimulated lymphocytes (Figure 2A). Compared to IP-10(1-77), about 3-fold higher concentrations of Met-IP-10 were required for a comparable chemotactic response. IP-10(3-77), however, was still inactive at concentrations as high as 10 nM. Thus, processing of IP-10 by CD26/DPP IV resulted in a 30-fold reduction in lymphocyte chemotactic activity. Similar results were observed with truncated compared to intact IP-10 on anti-CD3-activated lymphocytes (Figure 2B), although these cells were less sensitive to IP-10-induced chemotaxis than PHA-stimulated lymphocytes. This observation correlates with the reported lower expression of CXCR3 on anti-CD3-stimulated cells.5
Effect of CD26/DPP IV on the chemotactic and calcium signaling capacities of IP-10, Mig, and I-TAC on CXCR3-transfected cells Only one receptor for IP-10, that is, CXCR3, has been identified.6 Therefore, the chemotactic potencies of Met-IP-10, IP-10(1-77) and IP-10(3-77) were compared on CHO cells transfected with CXCR3 (Figure 3). For IP-10, a dose-dependent (minimal effective concentration of 3 nM) chemotactic response was observed, whereas for CD26/DPP IV-truncated IP-10(3-77) the minimal effective concentration (100 nM) was 30-fold higher. Even at 100 nM, Met-IP-10 failed to induce a significant chemotactic response. Intact Mig and I-TAC induced a significant chemotactic response on CXCR3-transfected cells at 10 nM (P < .01). In contrast, truncated Mig(3-103) and I-TAC(3-73) were inactive at concentrations as high as 100 nM. Although their NH2-terminal amino acid is different, removal of 2 amino acids (including the penultimate proline) resulted in a similarly impaired chemotactic activity of all 3 CXCR3 agonists.
Furthermore, it was observed that intact IP-10 and I-TAC induced a
significant increase in [Ca++]i at
concentrations higher than 0.3 nM, whereas 30-fold higher concentrations of Mig were required to obtain a detectable calcium response in CXCR3-transfected CHO cells (Figure
4). Met-IP-10 was about 3-fold less
potent compared to IP-10(1-77) and CD26/DPP IV-truncated IP-10 lacked
the calcium-signaling capacity through CXCR3. Indeed, although intact
IP-10 induced calcium mobilization at 1 nM, IP-10(3-77) was inactive in
the calcium assay at concentrations as high as 60 nM. Truncation of
I-TAC by CD26/DPP IV resulted in a 30- to 100-fold reduced calcium
signaling capacity for this CXCR3 ligand. In contrast, no significant
reduction in the weak calcium mobilizing capacity of Mig through CXCR3
could be observed for Mig(3-103). In conclusion, although none of
the 3 ligands possessed CXCR3-mediated chemotactic activity
after NH2-terminal truncation by CD26/DPP IV, Mig, but not
IP-10 or I-TAC, retained its rather weak calcium-signaling potency
through CXCR3.
Binding properties of intact and CD26/DPP IV-truncated CXCR3 ligands The capacity of truncated IP-10 to compete for binding of 125I-labeled intact I-TAC to peripheral blood-derived mononuclear cells was significantly decreased (Figure 5). 125I-labeled intact I-TAC was preferred over 125I-labeled intact IP-10 for the binding studies, because the commercially available 125I-labeled IP-10 has the extra NH2-terminal methionine. At concentrations of 100 nM, IP-10(3-77) displaced only 49% of the labeled I-TAC from the cells, whereas the displacement with 100 nM intact IP-10 was 88%. A comparable difference in binding competition capacity with 125I-labeled I-TAC to mononuclear cells was observed between intact and truncated I-TAC. On CXCR3-transfected cells, the binding affinity of IP-10(3-77) and I-TAC(3-73) was also clearly reduced (Figure 6). No significant difference in binding competition capacity to mononuclear cells was observed between both Mig forms although a tendency for reduced binding potency for the truncated Mig was observed. In addition, intact and truncated Mig could not significantly compete for 125I-I-TAC binding to CXCR3-transfected cells.
Calcium desensitization and chemotaxis antagonism with truncated CXCR3 ligands The CXCR3-transfected CHO cells were used to investigate whether inactive CD26/DPP IV-truncated IP-10(3-77) and I-TAC(3-73) could desensitize calcium signaling through CXCR3. Addition of 1 nM IP-10(1-77) 0.3 nM I-TAC(1-73) or 50 nM Mig(1-103) to the CXCR3-transfected cells resulted in an increase in [Ca++]i of at least 100 nM (Figure 4). When 100 seconds prior to these stimuli, 10 nM of inactive IP-10(3-77) or 3 nM of inactive I-TAC(3-73) was added to the cells, the increase in [Ca++]i was reduced by 30% to 40% (Table 2). Thus, truncated inactive CXCR3 ligands partially desensitize CXCR3 in calcium-signaling experiments.
Because IP-10(3-77) and I-TAC(3-73) failed to induce chemotactic
and calcium-signaling responses, but retained some receptor-binding properties, these truncated chemokines were tested as antagonists in
chemotaxis assays on CXCR3-transfected cells (Figure
7). Addition of an inactive concentration
of IP-10(3-77) (30 nM) to the lower well of the Boyden chamber resulted
in 70% reduction in chemotactic response toward 30 nM intact IP-10 and
in complete inhibition of the chemotactic activity of 10 nM intact
IP-10. However, truncated IP-10 failed to inhibit the chemotactic
response toward comparable concentrations of intact I-TAC. In contrast,
addition of truncated I-TAC(3-73) (30 nM) to intact I-TAC (10 nM or 30 nM) resulted in a 50% reduced chemotactic index.
Antiangiogenic activities of IP-10 processed by CD26/DPP IV When pellets containing 0.3 pmol natural human IL-8 were implanted into corneal micropockets on rabbit eyes, the induced neovascularization was maximal between days 5 and 7. Maximal inhibition of the angiogenic effect of IL-8 (0.3 pmol) was obtained by addition of 1 pmol intact IP-10 (Figure 8). CD26-truncated IP-10(3-77) equally inhibited IL-8-induced angiogenesis. At 1 and 3 pmol/pellet, no significant differences (Mann-Whitney U test, P > .2) between the antiangiogenic activities of intact and truncated IP-10 were observed. Comparable results were obtained when intact Mig(1-103) or CD26-truncated Mig(3-103) were used as angiogenesis inhibitors. Both intact and truncated Mig inhibited IL-8-induced angiogenesis. These data indicate that, in contrast to the inflammatory effect (chemotaxis), the angiostatic potential of IP-10 and Mig is either not mediated through CXCR3 or implicates alternative CXCR3-triggered signal transduction pathways.
During the past 2 decades, more than 50 human chemokines have been
identified. Chemokines and chemokine receptors form a complex network
that controls leukocyte migration during normal cell homing as well as
inflammatory processes. The receptor specificity of chemokines
determines the pattern of target cells. The expression of chemokines
and chemokine receptors is regulated at the transcriptional level by
different inducers. IFN- Recently, the highly specific protease CD26/DPP IV has been reported to
process a number of chemokines at the NH2 terminus with
different effects on their chemotactic and antiviral
activities.24,26 CD26/DPP IV is expressed on a wide
variety of cells including fibroblasts and epithelial and endothelial
cells. Moreover, CD26/DPP IV expression on CD45RO+ Th1
lymphocytes is further increased during activation. This protease
cleaves GCP-2, SDF-1, RANTES, eotaxin, macrophage-derived chemokine
(MDC), and the macrophage inflammatory protein-1 The chemotactic potency of the CXC chemokine SDF-1 and of the CC
chemokines RANTES, eotaxin, and MDC was drastically reduced on
NH2-terminal truncation by CD26/DPP IV.26
Accordingly, the binding affinity and calcium-signaling capacity of
truncated SDF-1, eotaxin, and MDC for their respective receptors CXCR4,
CCR3, and CCR4 decreased. Moreover, inhibition of CD26/DPP IV resulted
in prolonged protein kinase B activation by SDF-1 in T
cells.43 In contrast, treatment of the CC chemokine
LD78 So far, limited information is available on the role of CXCR3 in the angiostatic activity of IP-10. The reported expression of CXCR3 on microvascular endothelial cells is dependent on the cell cycle.19,20 Only proliferating, and not resting, microvascular endothelial cells are CXCR3+. However, no firm proof of the necessity of CXCR3 for the antiangiogenic effect of IP-10 and Mig has been given (eg, in receptor neutralization assays). Surprisingly, CD26/DPP IV-truncated IP-10 and Mig retained antiangiogenic activity in the rabbit cornea micropocket model. Consequently, CXCR3-mediated chemotactic activity and calcium signaling are no prerequisites for the angiostatic activity. Recently, also the murine, but not the human, CC chemokine 6C-kine (CCL21) has been reported to inhibit metastasis of human lung cancer cells in severe combined immunodeficient mice and to reduce tumor vascularity.46 Because murine, and not human, 6C-kine is a ligand for human CXCR3, these results suggest that CXCR3 is directly involved in the antiangiogenic effects of its ligands IP-10 and Mig. Thus, if CXCR3 is required for the antiangiogenic activity of IP-10, then the antiangiogenic and leukocyte chemotactic pathways use different signal transduction mechanisms. In fact, recent reports have shown that depending on the cell type multiple signal transduction pathways may be activated through CXCR3 including extracellular signal-regulated kinase (ERK), Src, and phosphatidylinositol-3 kinase (PI3K) signal cascades.47,48 Our results suggest that truncated IP-10 and Mig could activate some (those that are important for the antiangiogenic effect) but not all CXCR3 signal transduction pathways. Because IFN-
The authors thank René Conings, Jean-Pierre Lenaerts, Michel Op de Beeck, and Willy Put for technical assistance. Fresh human buffy coats were kindly provided by the Blood Transfusion Centers of Antwerp and Leuven, Belgium.
Submitted March 16, 2001; accepted July 31, 2001.
Supported by the Fund for Scientific Research of Flanders (FWO-Vlaanderen), the Concerted Research Actions of the Regional Government of Flanders, the InterUniversity Attraction Pole initiative of the Belgian Federal Government (IUAP), and the BIOMED Program of the European Community. P.P., A.W., S.S., P.M., and J.N. hold fellowships of the FWO-Vlaanderen.
M.D. is employed by Euroscreen SA, whose product, CHO-K1 cells transfected with CXCR3, is studied in the present work.
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: Paul Proost, Laboratory of Molecular Immunology, Rega Institute for Medical Research, K. U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium; e-mail: paul.proost{at}rega.kuleuven.ac.be.
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Top
Abstract
Introduction
-inducible protein-10 (IP-10), monokine induced by IFN-
-chemoattractant (I-TAC), share a
unique CXC chemokine receptor (CXCR3). Recently, the highly specific membrane-bound protease and lymphocyte surface marker CD26/dipeptidyl peptidase IV (DPP IV) was found to be responsible for posttranslational processing of chemokines. Removal of NH2-terminal
dipeptides by CD26/DPP IV alters chemokine receptor binding and
signaling, and hence inflammatory and anti-human immunodeficiency
virus (HIV) activities. CD26/DPP IV and CXCR3 are both markers for Th1
lymphocytes and, moreover, CD26/DPP IV is present in a soluble, active
form in human plasma. This study reports that at physiologic enzyme concentrations CD26/DPP IV cleaved 50% of I-TAC within 2 minutes, whereas for IP-10 and Mig the kinetics were 3- and 10-fold slower, respectively. Processing of IP-10 and I-TAC by CD26/DPP IV resulted in
reduced CXCR3-binding properties, loss of calcium-signaling capacity
through CXCR3, and more than 10-fold reduced chemotactic potency.
Moreover, IP-10 and I-TAC cleaved by CD26/DPP IV acted as chemotaxis
antagonists and CD26/DPP IV-truncated IP-10 and Mig retained their
ability to inhibit the angiogenic activity of interleukin-8 in the
rabbit cornea micropocket model. These data demonstrate a negative
feedback regulation by CD26/DPP IV in CXCR3-mediated chemotaxis without
affecting the angiostatic potential of the CXCR3 ligands IP-10 and Mig.
(Blood. 2001;98:3554-3561)
into NH2-terminally truncated
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