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J. Biol. Chem., Vol. 280, Issue 30, 27755-27758, July 29, 2005

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Inhibition of Membrane Type-1 Matrix Metalloproteinase by Cancer Drugs Interferes with the Homing of Diabetogenic T Cells into the Pancreas^*

Alexei Y. Savinov, Dmitri V. Rozanov, Vladislav S. Golubkov, F. Susan Wong, and Alex Y. Strongin¶

From the The Burnham Institute, La Jolla, California 92037 and Department of Pathology and Microbiology, University of Bristol, School of Medical Sciences, Bristol BS8 1TD, United Kingdom

Received for publication, June 2, 2005

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
We have discovered that clinically tested inhibitors of matrix metalloproteinases can control the functional activity of T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the onset of disease in a rodent model of type 1 diabetes in non-obese diabetic mice. We determined that MT1-MMP proteolysis of the T cell surface CD44 adhesion receptor affects the homing of T cells into the pancreas. We also determined that both the induction of the intrinsic T cell MT1-MMP activity and the shedding of cellular CD44 follow the adhesion of insulin-specific, CD8-positive, K^d-restricted T cells to the matrix. Conversely, inhibition of these events by AG3340 (a potent hydroxamate inhibitor that was widely used in clinical trials in cancer patents) impedes the transmigration of diabetogenic T cells into the pancreas and protects non-obese diabetic mice from diabetes onset. Overall, our studies have divulged a previously unknown function of MT1-MMP and identified a promising novel drug target in type I diabetes.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
Insulin-dependent diabetes mellitus (IDDM)¹ (type I diabetes) is a T cell-mediated, autoimmune disease. The pathogenesis of IDDM involves the activation of autoimmune T cells followed by their homing into the pancreatic islets (1). In the islets, T cells destroy insulin-producing cells (2). The CD44 surface receptor is elevated in activated T cells and, via its interactions with endothelial hyaluronan, contributes to T cell adhesion on the endothelium and the subsequent transmigration events (3). MT1-MMP, a multifunctional membrane-tethered enzyme, functions in cancer cells as one of the main mediators of pericellular proteolytic events and directly cleaves cell receptors (4, 5). CD44, a major hyaluronan receptor, is a well-established target of MT1-MMP in tumor cells (6–9). MT1-MMP cleavage releases the extracellular domain of CD44 from the cell surfaces and inactivates the functionality of the CD44 adhesion receptor. Evidence suggests that MT1-MMP proteolysis of CD44 significantly affects the adhesion and migration of malignant cells (6, 9, 10).

Consistently, we hypothesized that MT1-MMP also targets CD44 in T cells and that these proteolytic events regulate transmigration of the diabetogenic T cells into the pancreatic islets. In agreement with our hypothesis, we have determined here that pharmacological inhibition of T cell MT1-MMP enhances adhesion of the diabetogenic T cells to the pancreatic endothelium. Conversely, the enhanced adhesion of T cells significantly diminishes their subsequent homing into the pancreatic islets. Our results also imply that the inhibition of T cell MT1-MMP is key to the delay of the onset of diabetes in non-obese diabetic (NOD) mice, a well-accepted rodent model of IDDM.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
Mice and Cells—NOD mice of NOD/LtJ strain were obtained from the Jackson Laboratory. IS-CD8⁺ T cells (insulin-specific, CD8-positive, K^d-restricted T cells of the TGNFC8 clone from the pancreas of NOD mouse) (11) were maintained in Click's medium supplemented with 5% fetal calf serum, 2 x 10^-5 M -mercaptoethanol, 20 mM penicillin-streptomycin, 3 mg/ml L-glutamine, and 5 units/ml recombinant murine interleukin-2 (12). Every 3 weeks IS-CD8⁺ cells were mixed with irradiated NOD splenocytes (2000 rads) loaded with the L¹⁵YLVCGERG²³ insulin B chain peptide (10 µg/ml) (13). The animal treatment protocols have been reviewed and approved by The Burnham Institute review committee.

Induction of Diabetes in NOD Mice—IS-CD8⁺ cells were incubated both with and without AG3340 (50 µM or 21 µg/ml) for 2 h and then injected intravenously into the irradiated (725 rads, 24 h in advance), 5–8-week-old mice (1 x 10⁷ cells/animal). Mice were monitored for 21 days. On days 0, 2, 4, 6, 8, and 10 following the injection of the cells, mice received intraperitoneal injection with AG3340 (30 mg/kg or 1 mg/kg) or phosphate-buffered saline alone. The onset of diabetes was identified by assessing urine glucose levels with Diastix strips. Mice with urine glucose levels of >2000 mg/dl for 3 consecutive days were considered diabetic. AG3340 (molecular mass = 421 Da) was a kind gift of Dr. Peter Baciu (Allergan, Irvine, CA). According to numerous publications (e.g. Ref. 14), the level of glucose in the urine closely follows that in the blood. The measurement of glucose in urine is a widely accepted method to follow the development of diabetes in NOD mice (15).

Fluorescent Tracing and Morphometric Analysis—For trafficking studies, IS-CD8⁺ T cells were incubated at 1 x 10⁷ cells/ml for 30 min at 37 °C in the dark in complete Click's medium containing 5% fetal calf serum and 0.0075 mg/ml of the fluorescent dye 1,1'-didodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI; Molecular Probes). After incubation, the cells were washed three times with phosphate-buffered saline to remove excess DiI. Labeled IS-CD8⁺ cells (1 x 10⁷ cells) were injected intravenously in 0.2 ml of phosphate-buffered saline into irradiated (725 rads, 24 h in advance) NOD mice. Mice were sacrificed 24 h after injection of DiI-labeled cells. The spleen and the pancreata were excised and fixed in 0.1 M periodate-lysine-paraformaldehyde phosphate buffer. The organs were next sucrose-saturated, freeze-molded in OCT compound (Sakura Finetek Inc.), and freeze-sectioned. 7-µm-thick cryostat sections of the entire pancreas were prepared at 60-µm intervals using a Leica CM1900 cryotom. Distribution of DiI-labeled CD8⁺ cells within the islets was examined using a fluorescent microscope. At least 100 individual islets per mouse (4–5 mice/experimental group) were examined. The characteristic morphology of the islets is easily identified on the cryosections. DiI-labeled cells were counted within the area relevant to each individual islet (see Fig. 3 for a representative image; the islet-relevant area is depicted by the solid white line, and the islet boundaries are shown by the white dotted line). The position of each IS-CD8⁺ labeled cell was determined relative to the islet boundary. The labeled cells localized within the islet boundary were considered to be "inside," whereas the labeled cells adjacent to the islet but outside of the islet boundary were considered to be "at the entrance." This method was described in substantial detail in our prior work (12, 16).

Treatment of Cells with MT1-MMP-CAT—The catalytic domain of MT1-MMP (MT1-MMP-CAT; 3 µg) was co-incubated for 2 h at 37 °C with IS-CD8⁺ cells (1 x 10⁷ cells) in 0.2 ml of 50 mM HEPES, 10 mM CaCl₂, 0.5 mM MgCl₂, 50 µM ZnCl₂, and 0.01% Brij-35 buffer, pH 6.8. Where indicated, GM6001 (50 µM; Chemicon) was added to the samples. Following treatment, the cells were injected into the irradiated mice or used for DiI labeling, Western blotting, FACS analysis, and other analytical procedures (12, 17, 18).

Western Blotting—IS-CD8⁺ cells were surface biotinylated for 1 h at 4 °C with 0.1 mg/ml sulfo-NHS-LC-biotin (Pierce). Following washes to remove biotin, cells were co-incubated for 2 h with MT1-MMP-CAT in serum-free, unsupplemented Click's medium. The cells were then lysed with 50 mM N-octyl--D-glucopyranoside in phosphate-buffered saline supplemented with 1 mM CaCl₂, 1 mM MgCl₂, and protease inhibitor mixture containing phenylmethylsulfonyl fluoride (1 mM) and aprotinin, pepstatin, and leupeptin (1 µg/ml each). Biotin-labeled CD44 was captured from the cell lysate and from the medium aliquots on streptavidin-agarose beads. The captured samples were examined by Western blotting with the CD44 (clone IM7.8.1) antibody to determine the released, soluble, CD44 ectodomain in the medium samples and the residual, membrane-anchored, cellular CD44 in the cell lysates.

MT1-MMP-dependent MMP-2 Activation and Gelatin Zymography— IS-CD8⁺ cells (1 x 10⁶) were either allowed to adhere for 4 h in serum-free unsupplemented Click's medium to plastic coated with 2% gelatin or kept in solution. Under these experimental conditions, the vast majority of cells became attached to gelatin. In 4 h, media samples (30 µl each) were withdrawn and analyzed by gelatin zymography (17) to identify the proteolytic activity and the activation status of MMP-2 naturally synthesized by IS-CD8⁺ cells. Where indicated, cells were supplemented with external purified pro-MMP-2 (20 ng). Pro-MMP-2 was isolated from a conditioned medium of p2AHT2A72 cells derived from an HT1080 fibrosarcoma cell line sequentially transfected with the E1A and MMP-2 cDNAs (19).

Monoclonal Antibodies and FACS Analysis—IS-CD8⁺ cells were stained with the MT1-MMP (Ab815; Chemicon), CD44 (clone IM7.8.1), CD3 (clone 17A2), and CD49d (clone SG31) monoclonal antibodies (all from BD Biosciences) and the CD29 monoclonal antibody (Chemicon), followed by staining with fluorescein isothiocyanate- or phycoerythrin-conjugated secondary antibody (BD Biosciences), and then analyzed on a FACScan flow cytometer (Becton Dickinson). To determine the levels of CD44, IS-CD8⁺ cells were also stained with soluble fluorescently-labeled hyaluronan (Sigma). IS-C8⁺ cells were counterstained with phycoerythrin or fluorescein isothiocyanate-conjugated anti-CD8 antibody (Sigma).

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
MT1-MMP Sheds Cellular CD44—We determined that MT1-MMP proteolysis of T cell CD44 regulates adhesion and subsequent transmigration and homing of T cells into the pancreas.

FACS analyses with MT1-MMP and CD44 antibodies and fluorescein isothiocyanate-labeled hyaluronan demonstrated the presence of high levels of cell surface-associated MT1-MMP and CD44 in IS-CD8⁺ cells in suspension (Fig. 1A). IS-CD8⁺ cells recognize an insulin B chain-derived L¹⁵YLVCGERG²³ peptide in the context of the K^d major histocompatibility complex class I molecule (13). Injection of IS-CD8⁺ cells induces diabetes in sub-lethally irradiated NOD/LtJ mice in 1 week (12). NOD mice are widely used as the best animal model of IDDM (20). Because the Ab815 antibody against MT1-MMP recognizes the hinge domain of the protease, FACS tests do not distinguish the pro-enzyme, the activated enzyme forms, and the inert complexes of MT1-MMP with tissue inhibitors of metalloproteinases including tissue inhibitor of metalloproteinase-2.

View larger version (42K): [in this window] [in a new window]   FIG. 1. Excessive MT1-MMP proteolysis of CD44 decreases the rate of islet homing of T cells and delays the onset of diabetes in mice. A, FACS analyses of IS-CD8+ cells. IS-CD8+ cells were stained with the MT1-MMP and CD44 antibodies, followed by the fluorescein isothiocyanate-conjugated secondary antibody, and then subjected to FACS analyses. Similar results were obtained when CD44 was stained with soluble fluorescently labeled hyaluronan (data not shown). Left panel, staining of MT1-MMP (bold line, MT1-MMP; dotted line, isotype control). Right panel, staining of CD44 (bold line, untreated cells; dotted line, cells co-incubated with MT1-MMP-CAT). B, MT1-MMP sheds cellular CD44 and releases its soluble fragments into the medium. IS-CD8+ cells were surface biotinylated and then co-incubated with MT1-MMP-CAT (26). The cells were then lysed with N-octyl--D-glucopyranoside supplemented with a protease inhibitor mixture. Biotin-labeled CD44 was captured from the cell lysate, and the captured samples were examined by Western blotting with the CD44 antibody to determine the released, soluble, CD44 ectodomain (Medium) and the residual, membrane-anchored CD44 (Cells). Where indicated, GM6001 was added to the samples. C, MT1-MMP proteolysis of CD44 reduces diabetogenicity of IS-CD8+ cells. Left panel, cells were co-incubated with MT1-MMP-CAT, labeled with a fluorescent DiI dye, and then injected into NOD mice. In 24 h, the number of the labeled cells within the islets was counted in the cryostat sections of the pancreas. Right panel, MT1-MMP-CAT-treated and untreated IS-CD8+ cells were injected into NOD mice. The incidence of diabetes was 100% (6 of 6) with untreated cells and 70% (7 of 10) with the cells co-incubated with MT1-MMP-CAT.

IS-CD8⁺ cells co-incubated with MT1-MMP-CAT were also labeled with a fluorescent DiI dye and then injected into irradiated NOD mice. In 24 h, labeled cells were counted in the pancreatic islets. MT1-MMP proteolysis of CD44 caused an 4.5-fold decrease in cell homing and almost a 2-fold delay of the onset of diabetes in mice (Fig. 1C). These results suggested that cleavage of T cell CD44 by the external MT1-MMP-CAT decreased the number of the IS-CD8⁺ cells that were capable of adhering to hyaluronan of the pancreatic endothelium. Consequently, following co-incubation with MT1-MMP-CAT, the number of transmigrating cells was also low.

View larger version (61K): [in this window] [in a new window]   FIG. 2. Proteolytically active MT1-MMP activates MMP-2 and cleaves cellular CD44 in adherent IS-CD8+ cells. IS-CD8+ cells were either allowed to adhere to plastic coated with gelatin or kept in solution. Top panel, cells adherent to gelatin-coated plastic (A) and non-adherent cells in suspension (NA) were co-incubated with purified MMP-2 (MMP-2 alone; no cells). In 4 h, media samples were withdrawn and analyzed by gelatin zymography to identify the proteolytic activity and the activation status of MMP-2. To observe the activation of MMP-2 naturally synthesized by T cells, no external MMP-2 was added to the two samples on the left. P, I, and E, the 68-kDa pro-enzyme, the 64-kDa intermediate, and the active 62-kDa mature enzyme of MMP-2. Bottom panel, cells were either surface-biotinylated and allowed to adhere to gelatin or kept in suspension. Cell lysate and medium aliquots were captured with streptavidin-agarose beads. CD44 was analyzed in the captured samples by Western blotting with a CD44 antibody.

Inhibition of MT1-MMP Represses the Diabetogenicity of IS-CD8⁺ Cells—To confirm the role of MT1-MMP in T cell transmigration, homing, and diabetogenesis, we used another potent hydroxamate inhibitor, AG3340 (21). AG3340 inhibits MT1-MMP with a K_i in a sub-nanomolar range. AG3340 was used in cancer Phase I–III clinical trials (22). To evaluate AG3340, we used both IS-CD8⁺ cells and the splenocytes isolated from newly diabetic NOD mice (12). The cells were co-incubated with AG3340 or left untreated and then injected in NOD mice, which then received AG3340 (30 mg/kg and 1 mg/kg) or solvent alone (control). AG3340 at a concentration as low as 1 mg/kg delayed the onset of diabetes 2-fold compared with the control (Fig. 3A). These data are consistent with earlier work showing that inhibiting CD44 with neutralizing antibodies protects NOD mice from IDDM (23).

View larger version (60K): [in this window] [in a new window]   FIG. 3. A hydroxamate inhibitor, AG3340, inactivates MT1-MMP, blocks CD44 shedding in T cells, and delays the onset of transferred diabetes in NOD mice. A, AG3340 delays the onset of adoptively transferred diabetes in NOD mice. IS-CD8+ cells and the splenocytes were each injected intravenously into NOD mice (1 x 107 and 1.5 x 107 cells/mouse, respectively; 6 mice/group). On day 0, 2, 4, 6, 8, and 10 following injection of the cells, mice received intraperitoneal injection with AG3340 (30 and 1 mg/kg). B, AG3340 inhibits the transmigration of IS-CD8+ cells into the pancreatic islets. IS-CD8+ cells were co-incubated for 2 h with and without AG3340 (50 µM or 21 µg/ml) and then labeled with DiI. The labeled cells were next injected intravenously into NOD mice. In 24 h, the labeled cells at the entrance of the islet and within the pancreatic islets were each counted in the cryostat sections of the entire pancreas (12). n, total number of islets in each experimental group. C, representative images of the pancreatic islets from NOD mice that received injection with DiI-labeled IS-CD8+ cells. Images were taken 24 h after injection. Dotted line surrounds the islet. White solid line indicates the islet-relevant area, within which the DiI-labeled cells were counted. Bottom panel, cells were pre-incubated with AG3340; top panel, intact cells. Note that AG3340 blocks the entrance of IS-CD8+ cells into the islet. D, MT1-MMP proteolysis dynamically regulates the functionality of T cell CD44 in diapedesis. Low levels of MT1-MMP stimulate adhesion of T cells to the hyaluronan-rich endothelium. After T cell adhesion, T cell MT1-MMP is activated. High levels of MT1-MMP activity cause a CD44 deficiency. This event stimulates the transendothelial migration of T cells. Persistent CD44 excess reduces T cell homing and diapedesis.

Interestingly, injection of the broad spectrum MMP inhibitor KB-R7785 at 100 mg/kg twice daily (i.e. 200 mg/kg/day) for 4 weeks resulted in a significant decrease in plasma glucose levels in a rodent model of type II diabetes in KKAy mice. The proposed mechanism and the target proteins were, however, distinct from those determined in our model of type I diabetes (24). In addition, the dosages of the inhibitors used in our work were 100-fold lower. Additional studies that suggested the importance of MMP action in diabetes complications including cataract development, proteinuria, and periodontitis were reported by Ryan et al. (25). Overall, these earlier works and our studies imply that the broad spectrum MMP inhibitors may be used to control diabetes by targeting MT1-MMP and probably also disintegrin and metalloproteinase (ADAM)-like proteases (8).

We conclude that pharmacological inhibition of easily accessible, T cell surface-associated MT1-MMP by low dosages of the readily available anticancer hydroxamate class drugs will reduce transmigration of cytotoxic T cells into the pancreatic islets. We believe that our results have the potential for therapeutic translation and need further testing (which is in progress) in a spontaneous animal model of IDDM.

	FOOTNOTES

 
^* This work was supported by National Institutes of Health Grants CA83017, CA77470, and RR020843 (to A. Y. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Cancer Research Center, The Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-713-6271; Fax: 858-646-3192; E-mail: strongin{at}burnham.org.

¹ The abbreviations used are: IDDM, insulin-dependent diabetes mellitus; DiI, 1,1'-didodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; MMP, matrix metalloproteinase; MT1-MMP, membrane type-1 matrix metalloproteinase; MT1-MMP-CAT, the catalytic domain of MT1-MMP; NOD, non-obese diabetic; FACS, fluorescence-activated cell-sorting.

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TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 

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This Article Abstract Full Text (PDF) All Versions of this Article: 280/30/27755    most recent M506016200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Savinov, A. Y. Articles by Strongin, A. Y. Search for Related Content PubMed PubMed Citation Articles by Savinov, A. Y. Articles by Strongin, A. Y. Social Bookmarking                      What's this?