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At least 775 records · Page 43Linked to original sources
PubMed1999

Clostridium difficile toxins may augment bacterial penetration of intestinal epithelium.

BACKGROUND: Clostridium difficile can be recovered from many high-risk hospitalized patients receiving broad-spectrum antibiotic therapy. Clostridium difficile toxins A and B have been associated with increased intestinal permeability in vitro and there is growing evidence that increased intestinal permeability may be a common mechanism whereby enteric bacteria penetrate the intestinal epithelium. HYPOTHESIS: Clostridium difficile-induced alterations in the intestinal barrier facilitate microbial penetration of the intestinal epithelium, which in turn facilitates the translocation of intestinal bacteria. DESIGN: Mature Caco-2 enterocytes were pretreated with varying concentrations of toxin A or toxin B followed by 1 hour of incubation with pure cultures of either Salmonella typhimurium, Escherichia coli, or Proteus mirabilis. The effects of toxins A and B on enterocyte viability, cytoskeletal actin, and ultrastructural topography were assessed using vital dyes, fluorescein-labeled phalloidin, and scanning electron microscopy, respectively. The toxins' effects on bacterial adherence and bacterial internalization by cultured enterocytes were assessed using enzyme-linked immunosorbent assay and quantitative culture, respectively. Epithelial permeability was assessed by changes in transepithelial electrical resistance and by quantifying paracellular bacterial movement through Caco-2 enterocytes cultivated on permeable supports. RESULTS: Neither toxin A nor toxin B had a measurable effect on the numbers of enteric bacteria internalized by Caco-2 enterocytes; however, both toxins were associated with alterations in enterocyte actin, decreased transepithelial electrical resistance, and increased bacterial adherence and paracellular transmigration. CONCLUSION: Clostridium difficile toxins A or B may facilitate bacterial adherence and penetration of the intestinal epithelial barrier.

Bacterial Adhesion↗
PubMed1996

Expression of human neutrophil L-selectin during the systemic inflammatory response syndrome is partly mediated by tumor factor alpha.

BACKGROUND: Rolling of neutrophils on the vascular endothelium is a requisite step to transmigration to areas of infection or inflammation, and this is regulated in part by the neutrophil cell adhesion molecule L-selectin. OBJECTIVES: To compare L-selectin expression in patients with systemic inflammatory response syndrome (SIRS) and healthy age-matched control subjects and to determine whether tumor necrosis factor alpha modulates L-selectin expression on human neutrophils. SETTING: A tertiary care surgical intensive care unit at a university teaching hospital. SUBJECTS: Patients identified with SIRS (American College of Critical Care Physicians and Society of Critical Care Medicine criteria) were compared with healthy age-matched control subjects. Venous blood samples that were obtained from healthy laboratory control subjects were used to examine the time course of L-selectin expression. MAIN OUTCOME MEASURES: Neutrophil L-selectin expression was determined by flow cytometry in patients with SIRS and control subjects. Tumor necrosis factor alpha concentrations were determined in blood and exudative fluid from patients with SIRS. Neutrophil L-selectin expression was measured during a 45-minute time course in the presence of recombinant human tumor necrosis factor alpha and N-formyl-methionyl-leucyl-phenylalanine. RESULTS: Circulating neutrophils from patients with SIRS had significantly less L-selectin expression than did control subjects. Tumor necrosis factor alpha at concentrations similar to those found in exudative fluid caused a dose- and time-dependent decrease in neutrophil L-selectin expression. CONCLUSION: Tumor necrosis factor alpha may act as a paracrine modulator of site-specific neutrophil rolling, adhesion, and exudation via mechanisms that involve the down-regulation of L-selectin.

Age Factors↗
PubMed1996

Exudative neutrophils show impaired pH regulation compared with circulating neutrophils.

OBJECTIVE: To investigate the effects of neutrophil (PMN) transmigration into inflammatory sites on cytosolic pH (pHi) regulation. DESIGN: Exudative PMNs were obtained by bronchoalveolar lavage from rats sustaining endotoxin-induced lung injury. Circulating PMNs were purified with density-gradient centrifugation. Cytosolic pH was measured with single-cell fluorescence imaging using the pH-sensitive dye biscarboxyethyl-carboxyfluorescein. RESULTS: Exudative PMNs showed impaired pHi recovery from an induced acid load compared with circulating PMNs. Under conditions of extracellular acidosis, exudative PMNs showed impaired pHi homeostasis and produced decreased superoxide compared with circulating cells. Inhibition of the sodium-proton exchanger attenuated the differences in pHi recovery, suggesting a mechanism underlying the pHi regulatory dysfunction. All cells had comparable adenosine triphosphate levels and superoxide production at physiologic extracellular pH. CONCLUSION: Impaired pHi regulation of exudative cells may mediate cellular dysfunction and impaired resolution of infection at inflammatory sites.

Acidosis↗
PubMed1997

Liver endothelial E-selectin mediates carcinoma cell adhesion and promotes liver metastasis.

E-selectin is a cytokine-inducible endothelial cell adhesion receptor which is involved in the process of leukocyte rolling, the first in a cascade of interactions leading to leukocyte transmigration. Several studies have implicated this receptor in carcinoma cell adhesion to the endothelium, an interaction thought to be required for tumor extravasation during metastasis. To study the role of this receptor in the process of metastasis, we utilized a murine carcinoma line H-59 which is highly metastatic to the liver in vivo. When adhesion of H-59 cells to primary cultures of murine hepatic endothelial cells was measured, it was found that the tumor cells had a low basal level of adhesion to the sinusoidal endothelial cells, which could be significantly and specifically augmented by pre-activation of the endothelial cells with rTNF alpha. This incremental increase in adhesion to the activated endothelium could be completely and specifically abolished by a neutralizing monoclonal antibody to murine E-selectin (MAb 9A9). Similar results were obtained with 2 highly metastatic human colorectal carcinoma lines, HM 7 and CX-1, but not with a second murine subline, M-27, which is poorly metastatic to the liver. To assess the role of E-selectin in metastasis to the liver in vivo, the effect of MAb 9A9 on experimental liver metastasis was evaluated using the syngeneic H-59 model. We show here that this antibody caused a marked, specific and Fc-independent inhibition of experimental liver metastasis, reducing the median number of metastases by 97% relative to the control groups. Our results provide evidence that endothelial E-selectin is a mediator of carcinoma metastasis to the liver.

Animals↗
PubMed1999

Radiation-induced normal tissue injury: role of adhesion molecules in leukocyte-endothelial cell interactions.

The late onset of necrosis and fibrosis in normal tissues can be a serious consequence of radiotherapy in cancer patients. Because radiation-induced vascular injury precedes the tissue damage, vascular injury is regarded as crucial in the pathogenesis of tissue damage. An understanding of the processes responsible is essential to develop strategies for the amelioration of radiation-induced normal tissue damage. Leukocyte infiltration is commonly observed at sites of irradiation and is likely to lead to the acceleration and/or induction of parenchymal atrophy, fibrosis and necrosis in normal tissues following radiotherapy. The molecular mechanisms mediating leukocyte infiltration of tissues during inflammation have been studied extensively. It is now well established that cell adhesion molecules (CAMs) expressed on leukocytes and endothelial cells control the trafficking of leukocytes from the blood vessel lumen in these conditions. CAMs including E (endothelial), P (platelet) and L (leukocyte)-selectins, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), beta1 and beta2 integrins and CD31 are involved in the cascade of events resulting in rolling, arrest and transmigration of leukocytes through the inflamed endothelium. Whether a similar sequence of molecular events induces leukocyte sequestration in irradiated normal tissues is not known. This review is focussed on the role of CAMs in radiation-induced leukocyte infiltration of normal tissues and the therapeutic implications of these findings.

Animals↗
PubMed1999

Involvement of the c-erbB-2 oncogene product in the EGF-induced cell motility of SK-OV-3 ovarian cancer cells.

The epidermal growth factor (EGF) induces the rapid formation of dendritic processes and the dissociation of SK-OV-3 ovarian cancer cells. The SK-OV-3 cell line is characterized by over-expression of the c-erbB-2 oncogene product (p185(c-erbB-2)). To investigate the role of p185(c-erbB-2) in cell motility, a c-erbB-2-specific single-chain antibody was expressed in SK-OV-3 cells using a retroviral expression vector. Eight individual clones expressing the single chain antibody were isolated. These clones have prominent retention of the cell-surface p185(c-erbB-2). The EGF-induced morphologic changes and cell motility of the single-chain-antibody-expressing clones were strongly inhibited, as observed in cell dissociation and in transmigration experiments. However, the suppression of p185(c-erbB-2) does not inhibit the motility signal elicited by 12-O-tetradecanoyl-phorbol-13-acetate. These data indicate that the c-erbB-2 oncogene product is essential to mediate the motility signal of EGF to SK-OV-3 ovarian cancer cells. The enhancement of tumor-cell motility may be partially responsible for the unfavorable prognosis of ovarian cancer with over-expression of c-erbB-2.

Cell Movement↗
PubMed1996

PECAM-1 (CD31) expression in the central nervous system and its role in experimental allergic encephalomyelitis in the rat.

The role of T cell activation associated adhesion molecules on lymphocyte traffic and the initiation of inflammation has received considerable attention. This study, using a new monoclonal antibody (mAb) TLD-3A12, describes the distribution of PECAM-1 (CD31), an Ig supergene family adhesion molecule thought to be important in leukocyte transmigration during inflammation, in rat lymphoid organs and spinal cord. PECAM expression within the CNS is confined to endothelial cells of the blood brain barrier (BBB). Induction of inflammation within the CNS using the adoptive transfer of myelin reactive CD4+ T cells results in the de novo expression of immune adhesion and accessory molecules in the spinal cord, while the level of PECAM appeared only mildly increased. The distribution of PECAM on CNS endothelial cells became more diffuse during EAE induction, possibly the result of endothelial cell activation. In vitro studies demonstrate a partial inhibition of antigen-specific CD4+ T cell proliferation following anti-PECAM mAb treatment. Treatment of Lewis rats with TLD-3A12 antibody prior to T cell injection and throughout EAE induction does not result in a delay in the onset of clinical signs or weight loss, nor does it decrease the incidence and severity of disease. These data suggest that the expression of PECAM by CNS endothelial cells is not a requirement for the initiation of inflammation and clinical signs of EAE following the adoptive transfer of encephalitogenic lymphocytes. Thus, cells requiring PECAM-1 to migrate and perform their pathogenic functions are not critical to the development of rat EAE.

Animals↗
PubMed1999

Cyclic strain stimulates monocyte chemotactic protein-1 mRNA expression in smooth muscle cells.

Hemodynamic forces are important determinants for the formation of atherosclerotic plaques. The recruitment of circulating monocytes into the arterial wall is an important step during atherogenesis. Monocyte chemotactic protein-1 (MCP-1) has been shown to be a key factor for monocyte transmigration. This study examined the effects of cyclic strain on MCP-1 mRNA expression levels of cultured rat aortic smooth muscle cells. The MCP-1 mRNA levels of aortic smooth muscle cells first increased as the duration of cyclic strain increased, reaching the maximum at 6-12 h, maintained at high levels throughout the 48-h strain period. To explore signaling pathways mediating cyclic strain-stimulated MCP-1 mRNA expression, we examined the involvement of tyrosine kinase and protein kinase C (PKC). Tyrosine kinase inhibitors, genistein and tyrphostin 51, at 50 microM blocked cyclic strain-stimulated MCP-1 mRNA expression. Preincubation with a PKC activator, phorbol 12-myristate 13-acetate (PMA), 2 microM, for 24 h to downregulate PKC did not decrease cyclic strain-induced MCP-1 mRNA expression. A 6-h incubation with 0. 1 microM PMA to activate PKC, which stimulated MCP-1 expression when applied alone, abolished the stimulatory effects of cyclic strain. A specific PKC inhibitor, calphostin C (0.1 microM), diminished cyclic strain-stimulated MCP-1 mRNA expression. Angiotensin II at 10 or 1,000 nM induced a moderate upregulation of MCP-1 mRNA, and no synergistic effects were observed between angiotensin II and cyclic strain. These results indicate that cyclic strain stimulates MCP-1 mRNA expression in smooth muscle cells through signaling pathway(s) mediated by tyrosine kinase activation.

Angiotensin II↗
PubMed1998

Transforming growth factor-beta inhibition of cytokine-induced vascular cell adhesion molecule-1 expression in human astrocytes.

Leukocyte transmigration across the blood-brain barrier (BBB) is a cardinal feature of central nervous system (CNS) inflammation. Astrocytes form an integral part, both structurally and functionally, of the BBB. Vascular cell adhesion molecule-1 (VCAM-1), a member of the immunoglobulin gene superfamily, is involved in extravasation into inflamed tissues and activation of T-lymphocytes. In this study, we investigated the role of TGF-beta, an immunosuppressive cytokine, in regulating cytokine-induced VCAM-1 expression in astrocytes. Human astroglioma cell lines and primary human fetal astrocytes were examined for VCAM-1 gene expression after treatment with proinflammatory cytokines (TNF-alpha, IL-1beta, IFN-gamma) in the absence or presence of TGF-beta. Astroglioma cell lines as well as primary human fetal astrocytes expressed low levels of VCAM-1 constitutively, and the proinflammatory cytokines induced marked increases in VCAM-1 expression, particularly TNF-alpha and IL-1beta. The inclusion of TGF-beta1 or TGF-beta2 with the proinflammatory cytokines inhibited VCAM-1 gene expression to varying degrees (33-93%) in all the astroglioma cell lines and primary fetal cells. These results indicate that TGF-beta is an important regulator of cytokine induced VCAM-1 expression on astrocytes and may prove useful clinically in controlling CNS inflammation.

Astrocytes↗
PubMed1998

Contribution of CD11a/CD18, CD11b/CD18, ICAM-1 (CD54) and -2 (CD102) to human monocyte migration through endothelium and connective tissue fibroblast barriers.

Recently we reported that monocyte migration through a barrier of human synovial fibroblasts (HSF) is mediated by the CD11/CD18 (beta2) integrins, and the beta1 integrins VLA-4 and VLA-5 on monocytes. Here we investigated in parallel the role of beta2 integrin family members, LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) on monocytes, and the immunoglobulin supergene family members, ICAM-1 and ICAM-2 on HSF and on human umbilical vein endothelial cells (HUVEC), in monocyte migration through HSF and HUVEC monolayers. Using function blocking monoclonal antibodies (mAb), when both VLA-4 and VLA-5 on monocytes were blocked, treatment of monocytes with mAb to both LFA-1 and to Mac-1 completely inhibited monocyte migration across HSF barriers, although blocking either of these beta2 integrins alone had no effect on migration, even when VLA-4 and VLA-5 were blocked. This indicates that optimal beta2 integrin-dependent monocyte migration in synovial connective tissue may be mediated by either LFA-1 or Mac-1. Both ICAM-1 and ICAM-2 were constitutively expressed on HSF and on HUVEC, although ICAM-2 was only minimally expressed on HSF. Based on results of mAb blockade, ICAM-1 appeared to be the major ligand for LFA-1-dependent migration through the HSF. In contrast, both ICAM-1 and ICAM-2 mediated LFA-1-dependent monocyte migration through HUVEC. However, neither ICAM-1 nor ICAM-2 was required for Mac-1 -dependent monocyte migration through either cell barrier, indicating that Mac-1 can utilize ligands distinct from ICAM-1 and ICAM-2 on HSF and on HUVEC during monocyte transmigration.

Antigens, CD↗
PubMed2001

Neutrophils in chronic obstructive pulmonary disease.

Neutrophil accumulation in the lung is a prominent feature of chronic obstructive pulmonary disease (COPD) and the activation of these cells, producing proteases and oxygen-derived free radicals, is thought to be important in the pathogenesis of the disease. An important step in recruitment is the local generation of a neutrophil chemoattractant signal which mediates the trapping and firm adhesion of rolling neutrophils on the microvascular endothelium, followed by migration via intercellular junctions. Two neutrophil chemoattractants are particularly important in this respect, C5a generated by cleavage of complement C5 in interstitial fluid, and interleukin (IL)-8 synthesized by cells in the lung, e.g. macrophages, epithelial cells, endothelial cells, smooth muscle cells and neutrophils themselves. Lipid mediators, such as leukotriene B4 (LTB4), are also potentially important. Several studies have been carried out to investigate the role of IL-8 in COPD. IL-8 has been detected in bronchoalveolar lavage fluid and sputum from such subjects and in the systemic circulation. The levels of IL-8 have been found to correlate with neutrophil numbers and markers of neutrophil activation, such as myeloperoxidase activity. Some studies have also found a correlation between IL-8 levels, neutrophil numbers and the degree of lung dysfunction. These parameters are insensitive to steroids. Thus, the mechanisms involved in neutrophil recruitment, i.e. chemoattractant secretion or action, adhesion and endothelial transmigration, are important potential targets for the development of novel therapy. The IL-8 receptors on neutrophils, CXCR1 and CXCR2, are of particular interest.

Animals↗
PubMed1977

On the histology of human seminoma: development of the solid tumor from intratubular seminoma cells.

Intratubular seminomas of the testis associated with solid tumors were studied by light and electron microscopy in order to obtain information about the earliest stage of emigration from the tubules and invasion of the interstitial space. Careful examination of numerous sections reveals that at this stage neoplastic cells protrude into evaginations of the tubule covered by basement membrance or directly invade that membrane. At the site of tumor cell emigration, the basement membrane is thickened and multilayered. Tumor cells devoid of basement membrane were found in the interstitium. Their transmigration through the basement membrane was never observed. Subsequent to the migration of seminoma cells the tubules are smaller in diameter and contain only Sertoli cells. From the observations described it is inferred that tumor cells in the interstitial tissue increase in number, form strands and lobules, and finally build up the solid tumor.

Adult↗
PubMed2001

Integrin expression at the bone/biomaterial interface.

The aim of this study was to visualize integrin expression by cells in interface tissue in relation to their ligands. Tissue samples were obtained from 25 patients undergoing revision of aseptically loose total joint replacements. Serial sections were immunolabeled for the integrins alpha(2)beta(1), alpha(v)beta(3), alpha(4)beta(1), alpha(L)beta(2) (CD11a), alpha(M)beta(2) (CD11b), and alpha(X)beta(2) (CD11c), and the ligands fibronectin, laminin, vitronectin, intercellular adhesion molecule-1, and vascular adhesion molecule-1. Most cells were found to express alpha(2)beta(1), most macrophages and giant cells expressed CD11b, and the majority of CD11a was found on perivascular T lymphocytes. From the small amount of alpha(4)beta(1) and vascular adhesion molecule-1 expression in the interface tissue and the combination of CD11a, CD11b, and intercellular adhesion molecule-1 expression, it would seem that macrophages use beta(2) integrins to transmigrate.

Aged↗
PubMed2000

HLA-G inhibits the transendothelial migration of human NK cells.

The expression of the non-classical MHC class I molecule HLA-G is normally restricted to the placenta during pregnancy, where it is found on fetal endothelial cells and on invasive cytotrophoblast cells, specifically those at the maternal / fetal interface. Its precise physiological role has yet to be defined. HLA-G may have nonimmune functions relating to angiogenesis and placentation, but most evidence suggests that it protects fetal cells from lysis by maternal uterine NK cells, which are found in large numbers around invading trophoblast cells. This effect is due to specific interaction with inhibitory receptors expressed on NK cells. We have examined the hypothesis that another function of HLA-G is to inhibit NK cell migration. Using an in vitro transmigration assay system, we present data to support this hypothesis. NK cell migration across porcine endothelial cells transfected with HLA-G1 was specifically inhibited compared to migration across HLA-A2-transfected monolayers. HLA- G1 had no influence on the migration of a control T lymphocyte line. These results support the idea that in vivo, HLA-G may inhibit NK cell traffic across the placenta.

Cell Movement↗
PubMed2001

Beta1 integrin activation on human neutrophils promotes beta2 integrin-mediated adhesion to fibronectin.

Although the importance of beta1 integrin-mediated binding to adhesion molecules and extracellular matrix (ECM) molecules is well established for most types of leukocytes, the expression patterns and functional importance of beta1 integrins on neutrophils have remained controversial. Using flow cytometry, we found that human neutrophils express the alpha4, alpha5, alpha9 and beta1 integrin subunits. To examine whether the integrins VLA-4 (alpha4/beta1) and VLA-5 (alpha5/beta1) have a functional role on neutrophils, we studied adhesion to their ligand fibronectin. Treatment of neutrophils with antibody 8A2, which specifically binds and activates beta1 integrins, resulted in increased binding to fibronectin. However, addition of blocking mAb revealed that 8A2-induced adhesion did not depend on beta1 integrins, but on the beta2 integrin CD11b/CD18. Similarly, activation of beta1 integrins by 8A2 resulted in CD11b-dependent binding of neutrophils to fibrinogen. 8A2 treatment increased expression of an activation epitope of CD11b/CD18, which depended on phosphoinositide 3-OH kinase activity and an adequate concentration of intracellular free Ca2+. These data suggest that engagement of beta1 integrins on neutrophils results in a cross-talk signal that leads to activation of the beta2 integrin CD11b/CD18, followed by CD11b-mediated adhesion. As transmigrated neutrophils are surrounded by both beta1 and beta2 ligands in the ECM, this integrin cross-talk could play a role in modifying migration and cellular activation in inflamed tissues.

Androstadienes↗
PubMed2001

Chemokine expression by systemic sclerosis fibroblasts: abnormal regulation of monocyte chemoattractant protein 1 expression.

OBJECTIVE: Chemokines are important mediators in the chemoattraction of leukocytes to sites of inflammation. This study investigated the potential contribution of systemic sclerosis (SSc) fibroblasts to chemokine production and its potential relevance to the pathogenesis of SSc. METHODS: The expression of messenger RNA (mRNA) for different C-C and C-X-C chemokines by SSc and normal fibroblasts was studied by RNase protection assay. Monocyte chemoattractant protein 1 (MCP-1) protein production was analyzed by enzyme-linked immunosorbent assay. The chemotactic effect of fibroblast-derived MCP-1 on monocytic cells was analyzed in a transmigration assay. Nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) activation in fibroblasts was studied by electromobility shift analysis. MCP-1 expression in SSc skin sections was studied by immunohistochemistry. RESULTS: Among all chemokine genes studied, only MCP-1 and interleukin-8 mRNA were expressed by nonstimulated normal and SSc fibroblasts. SSc fibroblasts displayed increased constitutive expression of MCP-1 mRNA and protein and showed a blunted response to oxidative stress. Increased MCP-1 production was associated with higher chemotactic activity for monocytic cells. Increased NF-kappaB or AP-1 activation was not responsible for the constitutive overexpression of MCP-1 by SSc fibroblasts. In SSc skin sections, MCP-1 expression was detected in fibroblasts, keratinocytes, and mononuclear cells, whereas it was undetectable in normal skin. CONCLUSION: SSc fibroblasts display a specific pattern of chemokine gene expression that is characterized by constitutively increased and abnormally regulated expression of MCP-1 in vitro. MCP-1 is also expressed in lesional skin and can participate in the pathogenesis of SSc.

Cells, Cultured↗
PubMed2001

Complex immunomodulatory effects of interferon-beta in multiple sclerosis include the upregulation of T helper 1-associated marker genes.

Multiple sclerosis (MS) is considered an autoimmune disease that is mediated by proinflammatory T helper-1 lymphocytes. The putative mechanism of interferon-beta (IFN-beta), an approved treatment for MS, includes the inhibition of T-cell proliferation, blocking of blood-brain-barrier opening and T-cell transmigration into the brain via interference with cell adhesion, and the upregulation of anti-inflammatory cytokines. In the present study, a gene expression analysis of IFN-beta-treated peripheral blood mononuclear cells by cDNA microarray documents the broad effects of IFN-beta that are not purely anti-inflammatory. Specifically, we addressed the effect of IFN-beta on T helper-1 differentiation- or lineage markers such as the IL-12 receptor beta2 chain and the chemokine receptor CCR5 that have been implicated in the pathogenesis of MS. Both markers were significantly upregulated in vitro and in vivo under IFN-beta therapy, supporting that this cytokine exerts complex effects on the immune system. The combination of cDNA microarray and quantitative PCR will expand our knowledge of the immunological effects of such pleiotropic agents as IFN-beta, may provide a key to why certain patients fail to respond, and eventually may influence our view of the disease pathogenesis.

Adjuvants, Immunologic↗
PubMed2001

Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-beta therapy in relapsing and secondary-progressive multiple sclerosis patients.

Matrix metalloproteinases (MMPs) have recently been implicated in the pathogenesis of multiple sclerosis. Their suggested role includes the disruption of the blood-brain barrier, immune cell transmigration into the central nervous system, and myelin degradation. The present study characterized the mRNA level of a wide spectrum of MMPs and tissue inhibitors of metalloproteinases (TIMPs) expressed by peripheral blood leukocytes from relapsing-remitting (n = 16) and secondary-progressive (n = 12) multiple sclerosis patients. The expression of the same MMPs and TIMPs was evaluated also in a prospective 12-month follow-up of 6 patients randomly chosen from each of the 2 groups during interferon beta-1a treatment. Reverse transcription-polymerase chain reaction assessment demonstrated elevated levels of MT1-MMP and MMP-7 mRNA levels in both groups of patients, and no significant differences in MMP-9 levels, compared with healthy controls. Divergent expression of MMP-2 between relapsing-remitting and secondary-progressive patients compared with controls was observed. Interferon-beta treatment was associated with significant suppression of MMP-9 and MMP-7 mRNA in relapsing-remitting patients, though no significant changes were observed in the secondary-progressive group. These results contribute to the understanding of the IFN-beta-mediated immunomodulatory and therapeutic effects in multiple sclerosis patients and also support evidence for distinct immune mechanism(s) underlying relapsing-remitting versus secondary-progressive multiple sclerosis. The study also suggests that MMPs may be considered as potential biomarkers for response to treatment as well as targets for immunotherapy in multiple sclerosis.

Adjuvants, Immunologic↗