| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Immunology Research Center, Institut Armand-Frappier, Université du Québec, Québec, Canada
 |
Abstract |
|---|
 Top Abstract IntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
The expression of MMPs is closely regulated by activating agents, including cytokines and cell adhesion molecules of the integrin family (8, 9, 10). In T cells, the expression of MMP-2 and MMP-9 has been extensively studied and shown to depend on the activation state following exposure to chemotactic factors or cytokines, such as IL-2 and IL-4 (11, 12, 13). Integrin-mediated adhesion of T cells to recombinant cell adhesion molecules showed that vascular cell adhesion molecule-1 (VCAM-1)/very late Ag-4 (VLA-4) interaction is sufficient to induce MMP-2 expression in T cells (14). Local concentration of MMP, however, is likely not to depend solely on the invading T cells, but also on stromal cells in close proximity. Indeed, we and others have shown that T cells could induce MMP-9 expression in a variety of cell lines, including monocytic and fibroblastic cells (15, 16).
There is an indication that MMP-9 is a key player in the dissemination of T lymphoma cells to peripheral tissues. Although TIMP-1 counterbalances MMP-9 bioactivity, clinically aggressive lymphomas have shown surprisingly elevated levels of both MMP-9 and TIMP-1 (17, 18, 19). This observation suggests that either the induction of MMP-9 and TIMP-1 are temporally separated, or that both genes are closely coregulated during the invasion process. It is indeed possible that the TIMP-1 inhibitory effect on MMP-9 is masked by its enhancing effect on cell growth, particularly in the case of T lymphoid cells (20). The transcriptional regulation of MMP-9 and TIMP-1 during the dissemination process of normal and transformed T cells is still, however, largely unknown. Their co-expression in lymphoma cells suggests that they could depend on a common induction mechanism. Alternatively, the observation that some lymphoma cell clones express MMP-9 and TIMP-1 separately supports the idea that their induction could be mediated by temporally separated transcriptional activation involving unique or distinct stimuli (19).
As vascular cells form a dynamic tissue capable of responding to its environment and/or activating cells through the production of cytokines and cell surface expression of cell adhesion molecules, we hypothesized that contact between T lymphoma cells and endothelial cells (EC) is a key event that controls expression of MMP-9 and TIMP-1 at the site of extravasation. In the present work, we have examined the expression of MMP-2 and MMP-9 mRNA and enzymatic activity, as well as the expression of their natural inhibitors, TIMP-1 and TIMP-2, during adhesion of LFA-1-positive T lymphoma cells to EC in vitro. We showed that interaction between T lymphoma cells and EC leads to the induction of MMP-9 in both cell types. The inducing signals were, however, very distinct. Whereas the induction of MMP-9 in EC was due to lymphoma-derived soluble factors, increased expression of MMP-9 in lymphoma cells required intercellular adhesion molecule-1 (ICAM-1)-mediated adhesion. We further found that the expression of TIMP-1 paralleled that of MMP-9 in T lymphoma cells, but did not necessitate LFA-1/ICAM-1 interaction. Together, these results demonstrate that firm adhesion of T lymphoma cells to ECs participates in the production of MMP-9 and TIMP-1 in both cell types through tightly coordinated bi-directional signaling pathways, and identify ICAM-1/LFA-1 as a key interaction in the up-regulation of MMP-9 in T lymphoma cells upon contact with endothelium.
|
Material and Methods |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
The mouse T lymphoma cell line 164T2 was established in vitro from a radiation-induced T cell lymphoma in C57BL/Ka mice, as previously described (21). The 164T2 cells develop into massive lymphoid tumors in kidneys, liver, and spleen, following their i.v. injection to syngeneic mice (41). They express CD3, LFA-1, ICAM-1, and ICAM-2 constitutively, but not VLA-4. As an in vitro model to study the T lymphoma-EC interaction, we have used the endothelioma cell line b-end.3. In addition to expressing the von Willebrand factor, they express a repertoire of cell adhesion molecules indistinguishable from normal endothelium (such as E- and P-selectins, VCAM-1, ICAM-1, CD31, ICAM-2, etc.), and up-regulate their expression following stimulation with inflammatory cytokines, such as IL-1 and TNF, with kinetics similar to those reported for primary ECs. The similarity of this cell line to primary ECs has been well established in previous reports and has therefore been extensively used by many investigators as an in vitro model to study the ability of leukocytes to interact with vascular endothelium (22, 23, 24, 25, 26). All cells were maintained in culture using RPMI 1640 medium supplemented with 10% FCS, 2 mM glutamine, 10 mM HEPES, and antibiotics (complete medium). The inflammatory cytokines were purchased from Genzyme (Cambridge, MA).
Adhesion of T lymphoma cells to ECs
To study the effect of adhesion of T lymphoma cells to ECs, b-end.3 cells (5 x 105) were grown to confluency in 60-mm tissue culture wells by overnight culture. T lymphoma cells (5 x 106) were resuspended into 2 ml of complete serum RPMI medium for 6, 12, and 24 h at 37°C, 5% CO2. Firm adhesion was evident at 6 h after addition of the T lymphoma cells. The cocultures were then washed twice with PBS and the adherent lymphoma cells were removed by washing with a warm solution containing trypsin (0.004% w/v) and EDTA (0.002% w/v) dissolved in PBS. This treatment allowed the removal of more than 95% of T lymphoma cells, leaving intact the EC monolayer, as assessed by flow cytometric analysis using mAbs to Thy1-2 Ag.
Coculture in transwells
Coculture experiments separating cells with polycarbonate membrane inserts with a 0.4-µm pore size (Trans-well; Costar, Cambridge, MA) were conducted after presoaking the inserts with 1 ml of complete medium and plating ECs in 60-mm tissue culture wells in 2 ml of complete RPMI medium. The ECs were grown to confluency, and 5 x 106 164T2 lymphoma cells were added in the upper chamber of the inserts. Cocultures were conducted for 6, 12, and 24 h. Total cellular RNA was then extracted from both lymphoma and ECs. In some experiments, blocking mAbs (50 µg/ml) were added 15 min before coculture experiments. The anti-ICAM-2 blocking mAb (IgG2a, clone 3C4) was kindly provided by Dr. T. A. Springer Center for Blood Research, Harvard Medical School, Cambridge, MA. Abs to LFA-1 (I21.7/7) and ICAM-1 (YN-1) were derived from hybridomas obtained from the American Type Culture Collection (Rockville, MD) and were purified by standard protein G chromatography.
RNA isolation and analysis
Total cellular RNA was isolated from lymphoma and ECs using the
Trizol reagent (Life Technologies, Mississauga, Canada) according to
the manufacturer’s instructions. First strand cDNA was prepared from 3
µg of total cellular RNA in 20 µl of reaction volume using 40 U of
M-MuLV reverse transcriptase (Boehringer Mannheim, Laval, Canada).
After reverse transcription, the MMP-9, TIMP-1, MMP-2, and TIMP-2 were
amplified using specific primers directed against the 5' end of the
transcripts (Table I
). Expression of
ß-actin (Stratagene, La Jolla, CA) and IL-1ß (Clontech, Palo Alto,
CA) mRNA was monitored using commercially available primers.
TIMP-2-specific primers were carefully chosen to react with the
different mRNA messages possibly resulting from alternative
polyadenylation/termination site usage observed previously (27).
Amplification was conducted using the PCR core kit (Boehringer
Mannheim). Thirty cycles of amplification were performed in an MJ
Research (Watertown, MA) Thermal cycler (model PTC-100TM) using the
following programmed step cycle: 94°C for 1 min, 58°C for 2 min,
and 72°C for 3 min. The amplification for each gene was in the linear
curve. Five to 10 µl of the reaction mixture was size separated on a
1.5% agarose gel, and specifically amplified products were detected by
ethidium bromide staining and UV transillumination. Semiquantitative
analysis was conducted using a computerized densitometric imager (Model
GS-670; Bio-Rad, Mississauga, Canada).
|
MMP activity of cell culture supernatants was determined as previously described (16). Briefly, supernatants (1 ml) were centrifuged at 1200 rpm for 10 min to remove contaminating cells and debris, and were lyophilized and resuspended in 500 µl of PBS. Aliquots of 20 µl were subjected to electrophoresis on a 7.5% SDS-PAGE containing 1 mg/ml of denatured collagen. After electrophoresis, the gel was washed to remove SDS and incubated in a renaturating buffer (50 mM Tris, 5 mM CaCl2, 0.02% NaN3, 1% Triton X-100) for 18 h at 37°C. The gels were stained with Coomassie brilliant blue and destained in 30% (v/v) methanol/10% (v/v) acetic acid. The proteolytic activity was identified as a clear band on a blue background. Quantitative analysis of activity was conducted using a computerized densitometric imager.
|
Results |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
To study the expression of MMPs and TIMPs upon adhesion of T
lymphoma cells to EC, the cells were cocultured using a confluent
monolayer of EC. In this coculture, most, if not all, T lymphoma firmly
adhered to EC, as evidenced by the necessity of using trypsin to detach
T lymphoma cells from EC. So the expression of MMP and TIMP gene
expression in both cells could be assayed separately, lymphoma cells
were detached at the indicated time after initiation of the coculture
(6 to 24 h) using a warm solution (37°C) of PBS containing a low
concentration of trypsin and EDTA, as previously described (14). Using
mAbs to Thy-1.2, we showed that more than 95% of T cells were removed
while less than 2% of EC were detached by this procedure (data not
shown). Following removal of T lymphoma cells from EC coculture, total
RNA extraction from EC cells was conducted by adding directly the
Trizol reagent to the intact monolayer. Total RNA was then extracted
from both cell preparations and subjected to semiquantitative reverse
transcriptase (RT)-PCR. The primers used for RT-PCR are listed in Table I
(28, 29), and had all been pretested for their functional integrity.
PCR control reactions were conducted using ß-actin-specific primers
to standardize the relative amount of cDNA templates in each reaction.
Our results showed that coculture of T lymphoma cells with EC induced
time-dependent de novo expression of MMP-9 and TIMP-1 genes in lymphoma
cells (Fig. 1). The detection of de novo
synthesis of MMP-9 mRNA observed at 6 h postcontact was consistent
with the results obtained in T lymphoma cells following exposure with
PMA (16, 30). A reproducible but low copy number of MMP-2 transcripts
were also detected in lymphoma cells in contact with EC, but
necessitated twofold more cDNA templates compared with MMP-9, TIMP-1,
and TIMP-2 genes. The induction of MMP-9 and of TIMP-1 genes appeared
to be transient, as indicated by the lower intensity of the PCR
products obtained from RNA of lymphoma cells in contact with EC for
24 h. The expression of TIMP-2 in lymphoma cells was constitutive
and was not modulated following coculture with EC. These results
suggested that MMP-9 and TIMP-1 were concomitantly induced in T
lymphoma cells following contact with EC.
|
). As observed with lymphoma
cells, MMP-9 was induced in EC early after contact (6–12 h) with
lymphoma cells. In contrast to lymphoma cells, however, TIMP-1, TIMP-2,
and MMP-2 were expressed constitutively in EC, and did not vary
significantly upon coculture with lymphoma cells. The different
repertoire of MMP and TIMP gene expression in both cell types confirmed
the successful separation of T cells from EC by the mild trypsin
treatment. Together, these results demonstrate that binding of lymphoma
cells to EC induced bi-directional signaling that regulates MMP and
TIMP gene expression.
|
To assess the production of MMP by lymphoma and EC, the presence
of the bioactive proteases was assessed by zymography in culture
supernatant obtained from both cells cultured separately with or
without prior contact. We found that constitutive production of MMP-9
(97 kDa) and MMP-2 (62 kDa) by T lymphoma cells cultured alone was
barely detectable (Fig. 3). Very low
levels of MMP-9 were detected in EC cultured alone, while they secreted
significant amounts of MMP-2 constitutively. The patterns of MMP
secretion by both cells before contact thus reflects the expression
observed by RT-PCR. The two bands observed of approximately 92 to 97
kDa likely correspond to the pro-MMP-9 (major band) and active forms of
MMP-9 (minor band), while the 62-kDa band represents the active forms
of MMP-2. When supernatants from overnight coculture of T lymphoma
cells and EC were tested, we found, as expected by the RT-PCR results
described above, a significant increase in MMP-9 production, while that
of MMP-2 did not change significantly. To establish whether the
increased concentration of MMP-9 was derived from both EC and lymphoma
cells, we separated both cell types after an initial contact and
cultured them separately for an overnight period at 37°C. Zymographic
analysis of the supernatants confirmed that production of MMP-9 upon
coculture originated from both cell types. No MMP-2 was detected in the
supernatant of T lymphoma cells.
|
To assess whether MMP-9 induction in both cells necessitated
direct contact, or was mediated by cytokine production, we compared the
induction of the MMP-9 gene in both cell types following direct contact
with the induction obtained in transwell cocultures. In the transwell
design, lymphoma cells (upper chamber) were separated from EC (lower
chamber) by a porous 0.4-µM membrane. After 6, 12, and 24 h of
coculture, cells were harvested and examined for MMP-9 expression.
Controls included cells cultured alone and cells cultured in direct
contact. Our results showed that the physical barrier of transwells
completely abrogated the ability of EC to induce MMP-9 in T lymphoma
cells (Fig. 4 upper
panel), suggesting that induction of MMP-9 in lymphoma
cells required direct contact with EC. In contrast, we still observed
an up-regulation of MMP-9 in EC following coculture with T lymphoma
cells using the transwells (Fig. 4 lower panel),
although the kinetic of induction was slower, likely due to the loss of
the local effect normally provided by cell proximity during
intercellular contact. These results demonstrate that up-regulation of
MMP-9 in T lymphoma cells and EC following contact is mediated in
response to distinct stimuli. The results obtained in coculture
chambers were confirmed by stimulation with conditioned medium as we
found that culture supernatant from the lymphoma cell culture was able
to induce MMP-9 expression in EC (data not shown), indicating that the
ability of lymphoma cells to induce MMP-9 in EC was constitutive, and
was not secondary to an initial contact with EC. As expected,
supernatants from EC culture had no effect on MMP-9 and TIMP-1
expression in T lymphoma cells (data not shown). Since TIMP-1 gene
expression paralleled that of MMP-9 in lymphoma cells, we next tested
whether up-regulation of the TIMP-1 gene in lymphoma cells also
required contact. Using the same transwell design, we found that
induction of TIMP-1 in T lymphoma cells by EC was also abolished when
both cells were physically separated (Fig. 5). These results raised the possibility
that expression of both MMP-9 and TIMP-1 in lymphoma cells following
contact with EC was regulated by a common stimulus.
|
|
VLA-4/VCAM-1-mediated intercellular adhesion is necessary for the
induction of MMP-2 in T cells (14). We have previously shown that the
164T2 T lymphoma cells do not express VLA-4, but constitutively express
high levels of LFA-1 (Y. St-Pierre, unpublished observations). On the
other hand, the b-end-3 cells express a large number of cell adhesion
molecules, including ICAM-1, ICAM-2, and VCAM-1 (24, 25). To determine
whether LFA-1-mediated adhesion played a role in the expression of
MMP-9 and TIMP-1 in T lymphoma cells following contact with EC, we
conducted a series of in vitro experiments using blocking Abs to LFA-1,
ICAM-1, and ICAM-2. We found that addition of anti-ICAM-1 and
anti-LFA-1 added separately significantly inhibited the ability of
EC to induce MMP-9 expression in lymphoma cells (Fig. 6). Addition of anti-LFA-1 and
anti-ICAM-1 together completely abolished the induction of MMP-9.
In contrast, the presence of the Abs did not inhibit the ability of EC
to induce TIMP-1 expression in lymphoma cells, indicating that the
concomitant expression of MMP-9 and TIMP-1 in lymphoma cells following
contact with EC involves distinct stimuli. The functional relationship
between LFA-1/ICAM-1 interaction and MMP-9 expression was specific, as
demonstrated first by the inability of mAb to ICAM-2 to block MMP-9
expression, and second by the inability of mAb to LFA-1 and ICAM-1 to
block induction of TIMP-1.
|
It is well known that vascular ECs are highly susceptible to
activation by exposure to inflammatory cytokines, such as IL-1 and TNF.
To determine whether these cytokines could be involved in the ability
of T cells to increase MMP-9 expression in EC, we examined the
expression of these cytokines in T lymphoma cells. Our results showed
that T lymphoma cells constitutively expressed mRNA messages for both
IL-1ß and TNF-
, but not those encoding IFN-
(Fig. 7A). To determine
whether these cytokines can induce MMP-9 expression in EC, we tested
their ability to stimulate MMP-9 expression and we found that exposure
of EC to these inflammatory cytokines does indeed induce the expression
of MMP-9, in a dose-response pattern (Fig. 7B).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
Our work further supports the previous observations that a functional relationship exists between MMP production by circulating T cells and intercellular adhesion to EC. In normal CD4-positive Th1 cell clones, up-regulation of MMP-2 protein, activity, and transient mRNA expression at the surface of murine CD4-positive Th1 cells is dependent upon adhesion to ECs through VLA-4/VCAM-1 interaction (14). The lack of VLA-4 expression on the lymphoma cell lines used in our study may be the reason for the weak induction of MMP-2 in lymphomas following contact with EC. Similarly, the functional relationship between LFA-1/ICAM-1 and MMP-9 may also explain the previously reported inability of purified ICAM-1 to induce MMP-2, and of purified VCAM-1 to induce MMP-9 expression in T cells (14). Thus, MMP-2 and MMP-9, which have similar substrate specificity, can both be induced in T cells following firm adhesion to EC, but through distinct adhesion mechanisms. In our system, however, stimulation of T lymphoma cells with anti-LFA-1 mAbs immobilized on plastic failed to induce MMP-9 expression (F. Aoudjit, unpublished observations), suggesting that while LFA-1/ICAM-1 interaction is essential to induce MMP-9 in T lymphoma cells, other as yet unidentified signals are necessary as well. This observation is consistent with the inability of purified ICAM-1 alone to induce any detectable gelatinolytic activity in T cells (14).
The repertoire of expression of TIMP that we observed was in agreement with previous studies that showed that TIMP-2, but not TIMP-1, is constitutively expressed in lymphoma cell lines of the T cell lineage (31). The observation that clinically aggressive lymphoma express high levels of TIMP-1 (17, 18, 19) may be indicative of an in vivo positive selection of clones with sustained expression of TIMP-1 following contact with EC. At first glance, one might conclude that the concomitant up-regulation of TIMP-1 and MMP-9 by T lymphoma cells is paradoxical, since increased expression of TIMP-1 may not favor tissue invasion despite increased MMP-9 production and secretion. This might not be the case, however, since recent results using transgenic models suggest that TIMP-1 expression in vivo can either increase or decrease tumor invasion in a tumor cell-specific manner (32, 33). In fact, there are indications that TIMPs can have growth stimulatory activity on certain cell types, including on lymphoma cells and tumors of various origins (20, 34). From the transcriptional point of view, our results are consistent with those of others showing that the TIMP-1 gene is highly inducible following exposure to inducing agents (35, 36, 37). Our data are also consistent with preferential coregulation of MMP-9 and TIMP-1 in lymphoma cells observed in malignant forms of human non-Hodgkin’s lymphoma, and that are thought to play an important role in controlling their biologic aggressiveness (38). The coregulation of these genes, however, is only temporal, since their induction upon contact with EC requires distinct signals, as evidenced by the requirement for LFA-1/ICAM-1 interaction in the case of MMP-9, but not of TIMP-1. The fact that these genes are sometimes expressed independently of each other in some non-Hodgkin’s lymphoma clones or in different T cell clones is thus likely to reflect prior exposure to only one stimulus (19).
Our results may also have a significant impact on the understanding of dissemination of lymphoma cells to peripheral tissues. Previous studies have shown that specific high endothelial venules recognition processes involving cell adhesion molecules are operative during lymphoid neoplasms and seem to influence tumor dissemination (39, 40). The T lymphoma cell line that we have used in this study has an invasive phenotype, as these cells injected i.v. give rise to massive tumors in peripheral tissues (41). It is thus possible that the expression of MMP-9 by lymphoma cells is implicated in the invasion of peripheral tissues by lymphoma cells. Interestingly, we have recently observed that ICAM-1-deficient mice were completely resistant to T cell lymphoma invasiveness,4 indicating that the functional relationship between MMP-9 and ICAM-1 is essential for the establishment of peripheral T lymphoid tumors. This conclusion is further supported by our results showing that the invasive phenotype of T lymphoma cells is manifested after homing, and that overexpression of MMP-9 in lymphoma cells increases the frequency of lymphoma development.5 Previous studies had also shown that mAbs to LFA-1 could at least partially inhibit lymphoma dissemination in mice (42, 43). The observed effect of anti-LFA-1 could thus very well be due to its ability to interfere with MMP-9 expression by lymphoma cells. This possibility is further supported by the study of Hauzenberger et al. (44), who reported that cross-linking by immobilized LFA-1 mAbs can trigger a general invasive phenotype on T cells.
Our results have shown that bi-directional signaling during contact
between lymphoma cells and ECs leads to high expression of MMP-9 in
both cell types. We established clearly, using transwells and
conditioned medium, that up-regulation of MMP-9 in EC was mediated by
soluble factors. The constitutive gene expression and production of
inflammatory cytokines, such as IL-1 and TNF, by lymphoma cells, and
the induction of MMP-9 in EC following exposure to these same
cytokines, strongly indicate that TNF- and IL-1, which previously
have been shown to regulate MMP expression, are among the soluble
factors that could trigger MMP-9 production in EC. Work is currently in
progress to identify the soluble factors present in the supernatant of
T lymphoma cells that are responsible for the induction of MMP-9
in EC.
In conclusion, we have shown that bi-directional signaling upon adhesion of T lymphoma cells to ECs is a determinant in the local equilibrium between MMPs and TIMPs, and identified ICAM-1/LFA-1 as a key interaction in the up-regulation of MMP-9 in T lymphoma cells. Further elucidation of the underlying signaling mechanisms is likely to provide new insights in the design of therapeutic targets for controlling lymphoma metastasis.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Yves St-Pierre, Immunology Research Center, Institut Armand-Frappier, P.O. Box 100, Laval, Québec, Canada H7N 4Z3. E-mail address:
3 Abbreviations used in this paper: MMP, matrix metalloproteinase; TIMP, tissue inhibitor of matrix metalloproteinases; EC, endothelial cells; ICAM, intercellular adhesion molecule; VCAM-1, vascular cell adhesion molecule-1; VLA-4, very late Ag-4; RT, reverse transcriptase.
4 F. Aoudjit, T. A. Springer, E. F. Potworowski, and A. Y. St-Pierre. Genetic ablation of intercellular cell adhesion molecule-1 confers resistance to lymphoma cell metastasis in peripheral organs. Submitted for publication.
5 Aoudjit, F., S. Masure, G. Opdenakker, E. F. Potworowski, and Y. St-Pierre. Increased thymic lymphoma frequency in mice following overexpression of matrix metalloproteinase-9. Submitted for publication.
Received for publication August 27, 1997. Accepted for publication November 20, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
. J. Biol. Chem. 267:15176.4 ß1 and L ß2. J. Immunol. 158:76.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  M. Iwata, M. Pillai, A. Ramakrishnan, R. C. Hackman, H. J. Deeg, G. Opdenakker, and B. Torok-Storb Reduced expression of inducible gelatinase B/matrix metalloproteinase-9 in monocytes from patients with myelodysplastic syndrome: correlation of inducible levels with the percentage of cytogenetically marked cells and with marrow cellularity Blood, January 1, 2007; 109(1): 85 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Stefanidakis and E. Koivunen Cell-surface association between matrix metalloproteinases and integrins: role of the complexes in leukocyte migration and cancer progression Blood, September 1, 2006; 108(5): 1441 - 1450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Di Girolamo, I. Indoh, N. Jackson, D. Wakefield, H. P. McNeil, W. Yan, C. Geczy, J. P. Arm, and N. Tedla Human Mast Cell-Derived Gelatinase B (Matrix Metalloproteinase-9) Is Regulated by Inflammatory Cytokines: Role in Cell Migration J. Immunol., August 15, 2006; 177(4): 2638 - 2650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Belanger and Y. St-Pierre Role of selectins in the triggering, growth, and dissemination of T-lymphoma cells: implication of L-selectin in the growth of thymic lymphoma Blood, June 15, 2005; 105(12): 4800 - 4806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Rosette, R. B. Roth, P. Oeth, A. Braun, S. Kammerer, J. Ekblom, and M. F. Denissenko Role of ICAM1 in invasion of human breast cancer cells Carcinogenesis, May 1, 2005; 26(5): 943 - 950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Van Themsche, T. Alain, A. E. Kossakowska, S. Urbanski, E. F. Potworowski, and Y. St-Pierre Stromelysin-2 (Matrix Metalloproteinase 10) Is Inducible in Lymphoma Cells and Accelerates the Growth of Lymphoid Tumors In Vivo J. Immunol., September 15, 2004; 173(6): 3605 - 3611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Stefanidakis, T. Ruohtula, N. Borregaard, C. G. Gahmberg, and E. Koivunen Intracellular and Cell Surface Localization of a Complex between {alpha}M{beta}2 Integrin and Promatrix Metalloproteinase-9 Progelatinase in Neutrophils J. Immunol., June 1, 2004; 172(11): 7060 - 7068. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-Q. Wang, P. Sun, and A. S. Paller Ganglioside GM3 Inhibits Matrix Metalloproteinase-9 Activation and Disrupts Its Association with Integrin J. Biol. Chem., July 3, 2003; 278(28): 25591 - 25599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Nelissen, I. Ronsse, J. Van Damme, and G. Opdenakker Regulation of gelatinase B in human monocytic and endothelial cells by PECAM-1 ligation and its modulation by interferon-beta J. Leukoc. Biol., January 1, 2002; 71(1): 89 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. De Noncourt, O. Robledo, T. Alain, A. E. Kossakowska, S. J. Urbanski, E. F. Potworowski, and Y. St-Pierre Leukocyte elastase in murine and human non-Hodgkin lymphomas J. Leukoc. Biol., October 1, 2001; 70(4): 585 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Baram, G. G. Vaday, P. Salamon, I. Drucker, R. Hershkoviz, and Y. A. Mekori Human Mast Cells Release Metalloproteinase-9 on Contact with Activated T Cells: Juxtacrine Regulation by TNF-{alpha} J. Immunol., October 1, 2001; 167(7): 4008 - 4016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Faveeuw, G. Preece, and A. Ager Transendothelial migration of lymphocytes across high endothelial venules into lymph nodes is affected by metalloproteinases Blood, August 1, 2001; 98(3): 688 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. G. Phillips, L. M. Birnby, A. Narendran, and W. L. Milonovich Nitric oxide modulates capillary formation at the endothelial cell-tumor cell interface Am J Physiol Lung Cell Mol Physiol, July 1, 2001; 281(1): L278 - L290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Opdenakker, P. E. Van den Steen, B. Dubois, I. Nelissen, E. Van Coillie, S. Masure, P. Proost, and J. Van Damme Gelatinase B functions as regulator and effector in leukocyte biology J. Leukoc. Biol., June 1, 2001; 69(6): 851 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Boulday, S. Coupel, F. Coulon, J.-P. Soulillou, and B. Charreau Antigraft Antibody-Mediated Expression of Metalloproteinases on Endothelial Cells : Differential Expression of TIMP-1 and ADAM-10 Depends on Antibody Specificity and Isotype Circ. Res., March 2, 2001; 88(4): 430 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hidalgo and S. G. Eckhardt Development of Matrix Metalloproteinase Inhibitors in Cancer Therapy J Natl Cancer Inst, February 7, 2001; 93(3): 178 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Giraudon, R. Szymocha, S. Buart, A. Bernard, L. Cartier, M.-F. Belin, and H. Akaoka T Lymphocytes Activated by Persistent Viral Infection Differentially Modify the Expression of Metalloproteinases and Their Endogenous Inhibitors, TIMPs, in Human Astrocytes: Relevance to HTLV-I-Induced Neurological Disease J. Immunol., March 1, 2000; 164(5): 2718 - 2727. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Creange, T. Sharshar, T. Planchenault, C. Christov, F. Poron, J.-C. Raphael, and R. K. Gherardi Matrix metalloproteinase-9 is increased and correlates with severity in Guillain-Barre syndrome Neurology, November 1, 1999; 53(8): 1683 - 1683. [Abstract] [Full Text]
|
|
|
|
|
|
C. Phan, A. W. McMahon, R. C. Nelson, J. F. Elliott, and A. G. Murray Activated Lymphocytes Promote Endothelial Cell Detachment from Matrix: A Role for Modulation of Endothelial Cell {beta}1 Integrin Affinity J. Immunol., October 15, 1999; 163(8): 4557 - 4563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Kossakowska, D. R. Edwards, C. Prusinkiewicz, M. C. Zhang, D. Guo, S. J. Urbanski, T. Grogan, L. A. Marquez, and A. Janowska-Wieczorek Interleukin-6 Regulation of Matrix Metalloproteinase (MMP-2 and MMP-9) and Tissue Inhibitor of Metalloproteinase (TIMP-1) Expression in Malignant Non-Hodgkin's Lymphomas Blood, September 15, 1999; 94(6): 2080 - 2089. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Nagase and J. F. Woessner Jr. Matrix Metalloproteinases J. Biol. Chem., July 30, 1999; 274(31): 21491 - 21494. [Full Text] [PDF]
|
|
|
|
|
|
F. Aoudjit, E. F. Potworowski, T. A. Springer, and Y. St-Pierre Protection from Lymphoma Cell Metastasis in ICAM-1 Mutant Mice: A Posthoming Event J. Immunol., September 1, 1998; 161(5): 2333 - 2338. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
