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At least 181 records · Page 10Linked to original sources
PubMed2006

Inhibitory effect of PPAR on the expression of EMMPRIN in macrophages and foam cells.

OBJECTIVE: Extracellular matrix metalloproteinase inducer (EMMPRIN) is a surface glycoprotein that can stimulate the production of several matrix metalloproteinases (MMPs), which are thought to play an important role in atherosclerotic plaque destabilization and rupture. In order to demonstrate the involvement of EMMPRIN in the process of atherosclerosis, we characterized its expression profile in macrophages and foam cells, as well as its potential modulation by peroxisome proliferator-activated receptors (PPARs) agonists. METHODS AND RESULTS: Through TaqMan real-time RT-PCR and Western blotting, we found the expression of both EMMPRIN mRNA and protein was significantly increased during phorbol 12-myristate 13-acetate (PMA)-induced monocyte differentiation into macrophages. However, the same results were not observed when macrophages were further induced to become foam cells by oxidized low-density lipoproteins (oxLDL). Both known PPARalpha agonist clofibrate and gamma agonist pioglitazone potently and specifically inhibited EMMPRIN expression in macrophages and foam cells. Moreover, this inhibition was associated with a decrease of MMP-9 secretion and activity as determined by ELISA and zymography. In addition, PPARgamma antagonist GW9662 reversed the inhibitory effect of PPARgamma on EMMPRIN protein expression. CONCLUSION: Our findings revealed an upregulation of EMMPRIN during monocyte differentiation into macrophages and foam cells. Both PPARalpha and gamma agonists inhibited EMMPRIN expression, which may contribute to their inhibition of MMP.

Basigin↗
PubMed2006

Inhibitory effects of statins on human monocarboxylate transporter 4.

Human MCT4 (SLC16A3) is responsible for the efflux of L-lactic acid from skeletal muscle cells and is essential for muscle homeostasis. However, the effects of monocarboxylate drugs, such as statins on the MCT4-mediated transport of L-lactic acid have not been elucidated. Inhibition of L-lactic acid transport mediated by MCT4 might to lead to collapse of muscle homeostasis. The aim of this study was to establish an MCT4 transfected cell line and to clarify the transport mechanism of L-lactic acid and the effects of statins on this transport system. Results of Western blot analyses and immunohistochemistry studies indicated that the expression of CD147 and MCT4-FLAG protein were observed and was displayed clear plasma membrane localization in CD147 and MCT4-FLAG co-transfected cell line (cm cells). Uptake of L-lactic acid in cm cells was significantly greater than that in cells transfected with a vector alone. L-lactic acid uptake was concentration-dependent with a K(m) value of 28.43+/-3.87 mM. The results of a previous study showing a K(m) value of 28.5 mM in hMCT4-expressed oocytes. Lipophilic statins significantly inhibited [(14)C] L-lactic acid uptake in a concentration-dependent manner. In contrast, the inhibitory effects of hydrophilic statins were very weak.

Animals↗
PubMed2006

Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/II trials.

PURPOSE: HAb18G/CD147 is a hepatocellular carcinoma (HCC)-associated antigen. We developed iodine (131I) metuximab injection (Licartin), a novel 131I-labeled HAb18G/CD147-specific monoclonal antibody Fab'2 fragment, and evaluated its safety, pharmacokinetics, and clinical efficacy on HCC in Phase I/II trials. METHODS AND MATERIALS: In a Phase I trial, 28 patients were randomly assigned to receive the injection in 9.25-, 18.5-, 27.75-, or 37-MBq/kg doses by hepatic artery infusion. In a multicenter Phase II trial, 106 patients received the injection (27.75 MBq/kg) on Day 1 of a 28-day cycle. Response rate and survival rate were the endpoints. RESULTS: No life-threatening toxic effects were found. The safe dosage was 27.75 MBq/kg. The blood clearance fitted a biphasic model, and its half-life was 90.56-63.93 h. In the Phase II trial, the injection was found to be targeted and concentrated to tumor tissues. Of the 73 patients completing two cycles, 6 (8.22%) had a partial response, 14 (19.18%) minor response, and 43 (58.90%) stable disease. The 21-month survival rate was 44.54%. The survival rate of progression-free patients was significantly higher than that of patients with progressive disease after either one or two cycles (p < 0.0001 or p = 0.0019). CONCLUSION: Iodine (131I) metuximab injection is safe and active for HCC patients.

Adolescent↗
PubMed2006

CD147 contains different bioactive epitopes involving the regulation of cell adhesion and lymphocyte activation.

CD147 is a leukocyte surface molecule which belongs to the immunoglobulin superfamily. It is broadly expressed on various cell types and is a lymphocyte activation-associated molecule. In order to study the function of CD147, five CD147 monoclonal antibodies (mAbs) were generated: M6-2F9; M6-1D4; M6-1F3; M6-1B9; and M6-1E9. Biochemical characterizations and cross-blocking experiments indicated that M6-1B9 and M6-1E9 recognize the same or contiguous epitopes on CD147. By employing COS transfectants expressing CD147 membrane-distal domain (domain 1) and membrane-proximal domain (domain 2), mAbs M6-2F9, M6-1D4, M6-1B9, and M6-1E9 were shown to recognize epitopes located on domain 1 of the molecule. Functional studies indicated that engagement of CD147 by mAbs M6-1B9 and M6-1E9 strongly inhibited lymphocyte proliferation induced by a CD3 mAb. In contrast, mAbs M6-2F9, M6-1D4, and M6-1F3 induced U937 homotypic cell aggregation. The results indicate that CD147 contains at least two bioactive domains. Epitopes responsible for induction of cell aggregation are different from those regulating lymphocyte activation.

Animals↗
PubMed2004

Induction of IL-10 in rat peritoneal macrophages and dendritic cells by glatiramer acetate.

Glatiramer acetate (GLAT) is a mixture of basic polypeptides that have been shown to suppress experimental autoimmune encephalomyelitis (EAE). As Copaxone, GLAT is approved for the treatment of relapsing-remitting multiple sclerosis (MS). Different immunomechanisms have been suggested to contribute to the beneficial effects of GLAT which rely on blockade of MHC class II molecules or cross-recognition with myelin basic protein (MBP). Because GLAT could also inhibit experimental autoimmunity not related to myelin proteins, we searched for additional, less-restricted immunomodulatory actions of GLAT. Using freshly isolated resident peritoneal macrophages from naive Lewis rats, it is shown that GLAT profoundly modulates cytokine secretion of the cells. In unseparated macrophages (MPhi) and MPhi of low density, GLAT enhanced constitutive and LPS-induced production of interleukin 10 (IL-10) while LPS-induced synthesis of tumor necrosis factor-alpha (TNF-alpha) was dose-dependently suppressed by GLAT. Although both basic proteins GLAT and MBP facilitated adherence of MPhi, MBP had opposite effects on cytokine production suggesting unique properties of GLAT. In contrast to MPhi, peritoneal mast cells produced only little amounts of cytokines. The inductive effect of GLAT on IL-10 production by antigen-presenting cells was also observed in bone marrow-derived rat dendritic cells (DCs) which, unlike MPhi, were not suppressed in their production of TNF-alpha. Induction of IL-10 in different antigen-presenting cells is a new immunomodulatory mechanism of GLAT. In part, it goes along with the inhibition of TNF-alpha and may be a common basis for the known beneficial effects of GLAT on various cellular autoimmune responses including MS.

Animals↗
PubMed2005

C-reactive protein-induced upregulation of extracellular matrix metalloproteinase inducer in macrophages: inhibitory effect of fluvastatin.

OBJECTIVE: Extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase (MMP)-9 were reported to be expressed at the macrophage-rich area in human coronary atherosclerotic plaque. We examined whether C-reactive protein (CRP) activates macrophages to express EMMPRIN and MMP-9 in vitro and whether statins inhibit it. METHODS AND RESULTS: Rat peritoneal macrophages were collected by peritoneal lavage, and were incubated in the presence or absence of CRP. CRP at 5 microg/ml increased the gene expression of EMMPRIN relative to GAPDH, measured by RT-PCR, by 1.67+/-0.07 fold at 24 h and by 1.85+/-0.49 fold at 48 h (both p<0.05). The gene expression of MMP-9 in the presence of CRP at 5 microg/ml was followed by 1.36+/-0.11 fold increase at 24 h and by 3.95+/-0.81 fold at 48 h (both p<0.05). CRP at 5 microg/ml for 48 h increased by 6 fold MMP-9 activity, measured by zymography, without affecting tissue inhibitor of metalloproteinases-1. Boiled CRP at 5 mug/ml for 48 h unaffected MMP-9 activity. Fluvastatin blocked the CRP-induced increases in EMMPRIN and MMP-9 expression and activity. Diphenylene iodonium, an inhibitor of NADPH oxidase, had a similar effect on MMP-9 activity. Fluvastatin suppressed the CRP-induced increases in 8-epi-prostaglandin F(2alpha) levels in the condition media. CONCLUSIONS: CRP is an activator for macrophages to enhance EMMPRIN and MMP-9 expression. Fluvastatin inhibits them presumably through its antioxidant effect.

Animals↗
PubMed2004

Apoptosis of vasopressinergic hypothalamic neurons in chronic diabetes mellitus.

The hyperosmolality associated with diabetes mellitus triggers an increase in neuronal activity and vasopressin production within magnocellular neurosecretory cells (MNCs) of the hypothalamic supraoptic nucleus (SON). In this study, we examined the effect of chronic diabetes on the function and survival of these neurons. After 6 months, but not 6 weeks, of streptozotocin (STZ)-induced diabetes, we observed an increase in the appearance of small hyperchromatic neurons and a decrease in SON neuronal density. A subpopulation of neurons within the SON at this time point demonstrated positive staining for cleaved caspase-3 and TUNEL, two markers of apoptosis. In addition, the number of vasopressin-positive neurons was decreased. Markers for apoptosis did not colocalize with vasopressin immunopositivity; this was probably due to a diabetes-induced degenerative process causing downregulation of vasopressin expression or depletion of neuropeptide. Although the phenotypes of the apoptotic neurons were not identified, other SON neurons including oxytocin-producing neurons are unlikely to be affected by chronic hyperglycemia. Microglial hypertrophy and condensation were also observed in the 6-month diabetic SON. Although upregulation of vasopressin production in response to acute hyperosmolality is adaptive, prolonged overstimulation of vasopressin-producing neurons in chronic diabetes results in neurodegeneration and apoptosis.

Animals↗
PubMed2006

M1 receptors play a central role in modulating AD-like pathology in transgenic mice.

We investigated the therapeutic efficacy of the selective M1 muscarinic agonist AF267B in the 3xTg-AD model of Alzheimer disease. AF267B administration rescued the cognitive deficits in a spatial task but not contextual fear conditioning. The effect of AF267B on cognition predicted the neuropathological outcome, as both the Abeta and tau pathologies were reduced in the hippocampus and cortex, but not in the amygdala. The mechanism underlying the effect on the Abeta pathology was caused by the selective activation of ADAM17, thereby shifting APP processing toward the nonamyloidogenic pathway, whereas the reduction in tau pathology is mediated by decreased GSK3beta activity. We further demonstrate that administration of dicyclomine, an M1 antagonist, exacerbates the Abeta and tau pathologies. In conclusion, AF267B represents a peripherally administered low molecular weight compound to attenuate the major hallmarks of AD and to reverse deficits in cognition. Therefore, selective M1 agonists may be efficacious for the treatment of AD.

ADAM Proteins↗
PubMed2004

Developmental expression of methyl-CpG binding protein 2 is dynamically regulated in the rodent brain.

The gene encoding methyl-CpG binding protein 2 (MeCP2) is mutated in the large majority of girls that have Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. To better understand the developmental role of MeCP2, we studied the ontogeny of MeCP2 expression in rat brain using MeCP2 immunostaining and Western blots. MeCP2 positive neurons were present throughout the brain at all ages examined, although expression varied by region and age. At early postnatal ages, regions having neurons that were generated early and more mature had the strongest MeCP2 expression. Late developing structures including cortex, hippocampus and cerebellum exhibited the most significant changes in MeCP2 expression. Of these regions, the cerebellum showed the most striking cell-specific changes in MeCP2 expression. For example, the early-generated Purkinje cells became MeCP2 positive by P6, while the late-generated granule cells did not express MeCP2 until the fourth postnatal week. The timing of MeCP2 expression in the granule cell layer is coincident with the onset of granule cell synapse formation. Although more subtle, the degree of MeCP2 expression in cortex and hippocampus was most closely correlated with synaptogenesis in both regions. Our finding that MeCP2 expression is correlated with synaptogenesis is consistent with the hypothesis that Rett Syndrome is caused by defects in the formation or maintenance of synapses.

Aging↗
PubMedDate not supplied

Prenatal ethanol enhances rotational behavior to apomorphine in the 24-month-old rat offspring with small striatal lesion.

Pregnant Wistar rats received a hyperproteic liquid diet containing 37.5% ethanol-derived calories during gestation. Isocaloric amount of liquid diet, with maltose-dextrin substituted for ethanol, was given to control pair-fed dams. Offsprings were allowed to survive until 24 months of age. A set of aged female offsprings of both control diet and ethanol diet groups was registered for spontaneous motor activity, by means of an infrared motion sensor activity monitor, or for apomorphine-induced rotational behavior, while another lot of male offsprings was submitted to an unilateral striatal small mechanical lesion by a needle, 6 days before rotational recordings. Prenatal ethanol did not alter spontaneous motor parameters like resting time as well as the events of small and large movements in the aged offsprings. Bilateral circling behavior was already increased 5 min after apomorphine in the unlesioned offsprings of both the control and ethanol diet groups. However, it lasted more elevated for 45- to 75-min time intervals in the gestational ethanol-exposed offsprings, while decreasing faster in the control offsprings. Apomorphine triggered a strong and sustained elevation of contraversive turns in the striatal-lesioned 24-month-old offsprings of the ethanol group, but only a small and transient elevation was seen in the offsprings of the control diet group. Astroglial and microglial reactions were seen surrounding the striatal needle track lesion. Microdensitometric image analysis demonstrated no differences in the levels of tyrosine hydroxylase immunoreactivity in the striatum of 24-month-old unlesioned and lesioned offsprings of control and alcohol diet groups. The results suggest that ethanol exposure during gestation may alter the sensitivity of dopamine receptor in aged offsprings, which is augmented by even a small striatal lesion.

Age Factors↗
PubMed2003

Construction of high-density display of CD147 ectodomain on VCSM13 phage via gpVIII: effects of temperature, IPTG, and helper phage infection-period.

Production of VCSM13 phage displaying a high density of CD147 ectodomain (CD147Ex) was achieved when culturing conditions were modulated. A phagemid expressing CD147Ex was constructed and used to produce phage display CD147Ex gpVIII fusion protein in TG1 Escherichia coli. Displaying of CD147Ex via gpVIII was successfully increased when growing the transformed TG1 at 25 degrees C with IPTG-stimulation. In addition to temperature and IPTG-stimulation, the VCSM13 helper phage infection-period particularly affected the insertion of CD147Ex into phage progeny. By sandwich ELISA, incorporation of the CD147Ex into phage particle was confirmed. The correct size of the CD147Ex-gpVIII fusion protein at 28kDa was demonstrated by Western immunoblotting. Multivalent display of CD147Ex on phage particles will be valuable in discovering its ligand partner.

Antigens, CD↗
PubMed2004

Polarized lactate transporter activity and expression in the syncytiotrophoblast of the term human placenta.

We investigated the polarization of l-lactate transport in human syncytiotrophoblast by measuring uptake of [(14)C] l-lactate by both microvillous (maternal-facing; MVM) and basal (fetal-facing; BM) plasma membranes. [(14)C] l-lactate uptake by MVM and BM was stimulated in the presence of an inwardly directed H(+)gradient, with a significantly higher uptake in MVM than in BM at initial rate (15.4+/-2.3 vs 5.6+/-0.6 pmol/mg protein/20 sec). Stereospecific inhibition was observed in MVM, with a higher affinity for l-lactate compared with d-lactate. In BM, there was no difference in the inhibition by these two stereoisomers. Inhibition of lactate uptake in both MVM and BM by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of monocarboxylate transporter (MCT) activity, indicated MCT-mediated mechanisms across both membranes. Kinetic modelling supported a two-transporter model as the best fit for both MVM and BM, the K(m)of the major component being 6.21 mm and 25.01 mm in MVM and BM respectively. Western blotting and immunolocalization examining the distribution of MCT1 and MCT4, showed that MCT expression was polarized, MCT1 being predominantly localized to BM and MCT4 showing greater abundance on MVM. CD147, a chaperone protein for MCT1 and MCT4, was equally expressed by both membranes. These studies demonstrate that the opposing plasma membranes of human syncytiotrophoblast are polarized with respect to both MCT activity and expression.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2005

Red blood cell age determines the impact of storage and leukocyte burden on cell adhesion molecules, glycophorin A and the release of annexin V.

The influence of the age of the red blood cell (RBC) within its 120-day lifecycle at the time of blood donation on the RBC storage lesion is not well understood. Expression of cell adhesion molecules (CAMs) (CD44, CD47, CD58 and CD147), glycophorin A (GPA) and phosphatidylserine (PS) on young and old RBCs density separated prior to storage of the RBC concentrate was determined by flow cytometry. Older RBCs showed significantly reduced expression of GPA throughout storage and CD44 and CD147 from Day 28 onwards compared to young RBCs. Storage in the presence of leukocytes caused a significant decline in the expression of CD44, CD58, CD147 and GPA, whereas RBCs that were pre-storage leukocyte depleted maintained a relatively consistent level of expression throughout storage. PS was not detected at the external RBC membrane of young or old RBCs during storage. Increased levels of annexin V were detected in the supernatant of RBCs stored in the presence of leukocytes, with significantly greater supernatant levels found for old RBCs compared to young RBCs. These findings provide new insight into the RBC storage lesion and indicate that RBC age at the time of donation impacts upon the quality of stored RBC concentrates.

Aging↗
PubMed2006

Expression of CD147 and monocarboxylate transporters MCT1, MCT2 and MCT4 in porcine small intestine and colon.

Lactate, formed mainly in the stomach and small intestines, and short-chain fatty acids (SCFAs) formed in the colon, are ionised and require transporter proteins such as monocarboxylate transporters (MCTs) for absorption. The amounts of MCT1, MCT2, MCT4 and CD147, an ancillary protein for MCT1 and MCT4, were measured by immunoblotting the small intestine and colon of 40 pigs (Landrace, Yorkshire and LandracexYorkshire). MCT1 and MCT4 were found in both small intestine and colon, but MCT2 only in the small intestine. In both small intestine and colon, Yorkshire pigs had more CD147 than Landrace pigs, while no interbreed differences were found in MCT isoforms. Since CD147 is essential for the activity of MCT1 and MCT4, the breed difference suggests that MCT activity is higher in Yorkshire than in Landrace pigs. The absence of MCT2 in the colon suggests that it is mainly a lactate transporter, while MCT1 and MCT4 facilitate the transport of both lactate and SCFA.

Amino Acid Sequence↗
PubMed2006

Resveratrol inhibits macrophage expression of EMMPRIN by activating PPARgamma.

The effect of resveratrol on macrophage EMMPRIN expression and its potential mechanism was investigated. Both EMMPRIN expression and MMP-9 activity, respectively assayed by Western blot and zymography, were greatly up-regulated during PMA-induced macrophage differentiation from THP-1 monocytes. Both resveratrol and a PPARgamma agonist, pioglitazone, significantly inhibited EMMPRIN expression and MMP-9 activity in a concentration-dependent manner. The effects of pioglitazone and resveratrol were reversed by pretreatment of THP-1 cells with a PPARgamma antagonist, GW9662, prior to PMA induction. Thus, data suggest that resveratrol may down-regulate EMMPRIN and MMP-9 through PPARgamma activation. This possibility was further examined in resveratrol-or pioglitazone-treated U937 cells, which had been co-transfected with a PPARgamma expression vector and a luciferase reporter vector containing three tandem repeats of PPRE in cis. Results of the agonist-activated luciferase assay showed that resveratrol activated PPARgamma in a concentration-dependent manner. Since EMMPRIN and MMP-9 up-regulation is associated with activation of the NF-kappaB pathway, we investigated the effect of pioglitazone and resveratrol on TNF-alpha-induced NF-kappaB activation. Western blot results indicated that both pioglitazone and resveratrol markedly inhibited the NF-kappaB pathway through suppressing IkappaB protein phosphorylation in macrophages, although this effect of resveratrol was not reversed by GW9662. In conclusion, resveratrol can down-regulate EMMPRIN expression by macrophages via activating PPARgamma. This may be a primary mechanism of its inhibitory effect on MMP-9.

Anilides↗
PubMed2004

Direct cell-cell interaction enhances pro-MMP-2 production and activation in co-culture of laryngeal cancer cells and fibroblasts: involvement of EMMPRIN and MT1-MMP.

Matrix metalloproteinases-2 (MMP-2, gelatinase A) has been regarded as a crucial enzyme for tumor progression, invasion, and metastasis by its capability to degrade the basement membrane components, and its activation process is critical for tumor development. Recently, EMMPRIN/CD147, which is a member of immunoglobulin superfamily, has been reported to be highly expressed in tumor cells and induce production of MMPs from fibroblasts adjacent to the tumor cells. In this study, we demonstrated that production of pro- and active forms of MMP-2 by human dermal fibroblasts was enhanced by the direct cell-cell contact with co-cultured HEp-2 cells derived from a human laryngeal epidermoid carcinoma. The results from immunoblotting and reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated that HEp-2 cells express a higher level of EMMPRIN but only a low level of MMP-2 and membrane type 1-matrix metalloproteinase (MT1-MMP), whereas fibroblasts express a higher level of MMP-2 and MT1-MMP and a low level of EMMPRIN. In a mixed co-culture with direct cell-cell contacts, co-cultured HEp-2 cells stimulated the pro- and active MMP-2 production from fibroblasts, but not in a separated co-culture through polycarbonate membrane. Production of pro/active MMP-2 and MT1-MMP (activator of pro-MMP-2) in fibroblasts was induced by the addition of membrane fractions prepared from HEp-2 cells to the fibroblast culture, and the induction was suppressed by the EMMPRIN depletion after immunoprecipitation, signifying the participation of EMMPRIN for the induction and activation of MMP-2. Our results suggest an importance of the direct cell-cell interaction involving EMMPRIN rather than humoral factors such as cytokines for pro-MMP-2 production and activation followed by tumor progression, invasion, and metastasis in laryngeal cancer.

Antigens, CD↗
PubMed2005

Increased EMMPRIN (CD 147) expression during oral carcinogenesis.

Gene expression profiling of oral premalignant (OPM) cells and normal oral epithelial (NOR) cells showed that EMMPRIN expression was markedly upregulated in OPM cells compared to NOR cells. We used an oral squamous cell carcinoma (OSCC) progression model composed of cell lines, organotypic cultures and tissue specimens to characterize EMMPRIN expression patterns by microarray analysis, qRT-PCR, Western blotting and immunohistochemistry. EMMPRIN levels are elevated in OPM and primary and metastatic OSCC cells as compared to NOR. EMMPRIN was detected as high and low glycosylated forms in the OPM and OSCC cellular extracts and was released in the media by OSCC cells but not by OPM cells. EMMPRIN expression in an organotypic culture model of normal and OPM mucosae mirrored the expression patterns in the respective tissues in vivo. EMMPRIN expression was limited to basal cells of normal, benign hyperkeratotic and inflammatory (lichen planus) oral mucosa. EMMPRIN expression is increased in dysplastic leukoplakias spreading to more superficial layers, and its expression levels correlated significantly with the degree of dysplasia. Primary and metastatic OSCC showed strong cell surface expression of EMMPRIN. These results suggest that EMMPRIN overexpression occurs at a very early stage of oral carcinogenesis and plays a contributing role in OSCC tumorigenesis.

Aged↗
PubMed2005

Differential expression of extracellular matrix metalloproteinase inducer (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and matrix metalloproteinase induction.

Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally identified on the tumor cell surface as an inducer of matrix metalloproteinase (MMP) production in neighboring fibroblasts. Here we demonstrate a role for EMMPRIN in MMP induction during corneal wound healing. MMP and EMMPRIN expression was analyzed in normal and ulcerated human corneas, as well as in corneal epithelial and stromal cells in culture using confocal microscopy, zymography, immunoblots, and real-time polymerase chain reaction. In normal cornea EMMPRIN was predominantly expressed in the epithelium but was markedly induced in the anterior stroma of ulcerated corneas. This coincided with MMP-2 induction that co-localized with EMMPRIN at the epithelio-stromal boundary. The role of epithelial-stromal interaction in MMP induction was investigated in an in vitro co-culture system and demonstrated an induction and co-localization of EMMPRIN and MMP-2 in the fibroblasts at the interface with epithelial cells. Direct contact of fibroblasts with EMMPRIN-containing purified epithelial cell membranes also induced MMP-1, MMP-2, and EMMPRIN and this was inhibited by a blocking anti-EMMPRIN antibody, suggesting that EMMPRIN was primarily responsible for this induction. These findings, and the up-regulation of EMMPRIN by epidermal growth factor and transforming growth factor-beta, demonstrate a role for EMMPRIN in wound healing and suggest that sustained local up-regulation of EMMPRIN and MMPs in chronic situations in which healing is delayed may lead to excessive matrix degradation and corneal melts.

Antigens, CD↗