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PubMed2005

Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment.

Understanding the mechanisms of immune cell migration to multiple sclerosis lesions offers significant therapeutic potential. This study focused on the chemokines CXCL12 (SDF-1) and CXCL13 (BCA-1), both of which regulate B cell migration in lymphoid tissues. We report that immunohistologically CXCL12 was constitutively expressed in CNS parenchyma on blood vessel walls. In both active and chronic inactive multiple sclerosis lesions CXCL12 protein was elevated and detected on astrocytes and blood vessels. Quantitative PCR demonstrated that CXCL13 was produced in actively demyelinating multiple sclerosis lesions, but not in chronic inactive lesions or in the CNS of subjects who had no neurological disease. CXCL13 protein was localized in perivascular infiltrates and scattered infiltrating cells in lesion parenchyma. In the CSF of relapsing-remitting multiple sclerosis patients, both CXCL12 and CXCL13 were elevated. CXCL13, but not CXCL12, levels correlated strongly with intrathecal immunoglobulin production as well as the presence of B cells, plasma blasts and T cells. About 20% of CSF CD4+ cells and almost all B cells expressed the CXCL13 receptor CXCR5. In vitro, CXCL13 was produced by monocytes and at much higher levels by macrophages. CXCL13 mRNA and protein expression was induced by TNFalpha and IL-1beta but inhibited by IL-4 and IFNgamma. Together, CXCL12 and CXCL13 are elevated in active multiple sclerosis lesions and CXCL12 also in inactive lesions. The consequences of CXCL12 up-regulation could be manifold. CXCL12 localization on blood vessels indicates a possible role in leucocyte extravasation, and CXCL12 may contribute to plasma cell persistence since its receptor CXCR4 is retained during plasma cell differentiation. CXCL12 may contribute to axonal damage as it can become a neurotoxic mediator of cleavage by metalloproteases, which are present in multiple sclerosis lesions. The strong linkage of CXCL13 to immune cells and immunoglobulin levels in CSF suggests that this is one of the factors that attract and maintain B and T cells in inflamed CNS lesions. Therefore, both CXCL13 and CXCR5 may be promising therapeutic targets in multiple sclerosis.

Acute Disease↗
PubMed1979

Early onset and topographical distribution of hypertrophied astrocytes in hippocampus of aging rats: a quantitative study.

Our results indicate that the density of astrocytes exhibiting hypertrophy in the hippocampus increases dramatically and progressively with age, being significantly elevated even in mid-life (13 month) animals. However, the total population of astrocytic cells (hypertrophied and nonhypertrophied) in the quantified region is not significantly elevated. Further, the relative distributions of both hypertrophied and total glial cells remained remarkably constant at the three ages measured. Reactive hypertrophy of astrocytes therefore appears to occur "in place" and migration of astrocytes does not appear to be a major factor in the hippocampus during aging. Of particular note was the finding that astrocyte hypertrophy is far more prominent in synaptic terminal fields than in myelinated fibers of the same system.

Aging↗
PubMed1995

Interleukin-8 increases endothelial permeability independent of neutrophils.

Interleukin-8 (IL-8) has been associated with a variety of hyperinflammatory states and adverse clinical events. Circulating IL-8 levels correlate with the severity of tissue trauma, and excessive elevations of IL-8 are associated with postinjury adult respiratory distress syndrome and multiple organ failure. While IL-8 is a potent neutrophil (PMN) chemoattractant and activator and enhances PMN transendothelial migration, it also acts to inhibit PMN adhesion to stimulated endothelial cells (ECs). We hypothesized that IL-8 could interact directly with ECs to increase permeability independent of PMNs. Human umbilical vein ECs (HUVECs) were cultured on collagen-coated micropore filters, and integrity of the EC monolayer measured by albumin flux across the filter. Cytochalasin D was used as a positive control. IL-8 induced increased permeability at a concentration of 1000 ng/mL. This effect was abrogated by preincubation of HUVECs with a protein synthesis inhibitor (cycloheximide). These data suggest a role for IL-8 in promoting endothelial leak independent of PMNs, via a mechanism involving protein synthesis.

Cell Membrane Permeability↗
PubMed2001

FGF-8 in the ventral pharynx alters development of myocardial calcium transients after neural crest ablation.

Cardiac neural crest ablation results in depressed myocardial calcium transients and elevated proliferation in myocardium at a stage when cardiac neural crest cells are not in contact with the myocardium. To test the hypothesis that cardiac neural crest-derived cells, which migrate into the caudal, ventral pharynx at stage 14, block a signal from the ventral pharynx, we cultured stage 12 chick heart tube or myocardial strips in the presence or absence of ventral pharynx. We found that myocardium cultured with ventral pharynx that had not yet contacted neural crest cells had significantly reduced calcium transients and an increased rate of proliferation. Ventral pharynx from intact embryos at a stage when neural crest-derived cells had reached the pharynx had no effect on myocardial calcium transients. Ventral pharynx from neural crest-ablated embryos continued to suppress myocardial calcium transients at this later stage. Myocardium cultured with FGF-2 also showed a significant reduction in calcium transients. An FGF-2-neutralizing Ab reversed the deleterious effect of the ventral pharynx on myocardial calcium transients and proliferation. We therefore examined the expression of FGF-2 and similar FGFs in the ventral pharynx. Only FGF-8 was expressed in a temporospatial pattern that made it a viable candidate for altering the myocardial calcium transient during stages 14-18. In explant cultures, neutralizing Ab for FGF-8 rescued development of the myocardial calcium transient in neural crest-ablated chick embryos.

Animals↗
PubMed1986

1985 Kreshover lecture. Molecular factors influencing neutrophil defects in periodontal disease.

Major advances in our understanding of the role of the neutrophil in host defense against periodontal organisms have been made through studies of localized juvenile periodontitis (LJP). Several lines of evidence suggest that LJP is an infectious process closely associated with Actinobacillus (Haemophilus) actinomycetemomitans as a causative agent, although other organisms may also participate. The immunologic profile of LJP patients suggests that a cell-associated neutrophil locomotory dysfunction is a key underlying immunodeficiency resulting in increased susceptibility to periodontal infection. In addition, LJP patients often exhibit cervical lymphadenopathy and IgG-hypergammaglobulinemia, and a markedly elevated antibody response to the infecting organism, A. actinomycetemcomitans, is found in the serum and crevicular fluid of most patients. Evaluation of the locomotory properties of LJP neutrophils shows that random migration and chemokinesis are normal; however, about 70% of the LJP patients suffer from a defect in chemotaxis, with their neutrophils responding poorly to bacterial chemotactic factors, synthetic chemotactic peptides, and complement fragments (C5a). Depressed chemotaxis of LJP neutrophils is paralleled by their reduced capacity to bind the synthetic chemotactic peptide N-formylmethionylleucylphenylalanine (FMLP), as well as C5a. Furthermore, there is a reduction in the amount of glycoprotein 110, a neutrophil membrane matrix component and differentiation antigen which is associated with FMLP- and possibly also C5a-mediated chemotaxis. Reduction of C5a and of FMLP ligand binding, decreased expression of GP-110, and reduced neutrophil chemotaxis are consistent with a stem cell maturation error in LJP patients. This is further supported by studies demonstrating increased expression of CR2, the C3d/EBV receptor, on peripheral blood neutrophils of LJP patients. CR2 receptors are normally present on immature human neutrophils but are lost during the maturation process. These alterations in neutrophil surface components and their reduced chemotaxis may result from a genetically determined abnormality. Studies demonstrating the familial nature of both the neutrophil chemotactic disorder and the clinical entity represented by localized juvenile periodontitis point to a strong role for genetic determinants in the disease which affect neutrophil surface receptors.

Aggressive Periodontitis↗
PubMed1989

Neutrophil chemotactic factors in bacterial pneumonia.

The influx of neutrophils into the lung is a prominent feature in patients with bacterial pneumonia. Since neutrophils migrate in response to chemotactic factors, chemotactic activity was evaluated in bronchoalveolar lavage (BAL) fluid obtained from 12 patients with bacterial pneumonia and ten normal control subjects. Chemotactic activity was greatly elevated in the BAL fluid of the pneumonia patients compared with control subjects (p less than 0.01). To partially characterize the chemotactic factors present in the lavage fluid of the patient group, molecular sieve chromatography was performed on the lavage fluid, and at least three peaks of chemotactic activity were identified. Since the molecular weight of the smaller peaks approximated the molecular weight of two known chemotactic factors, C5a and leukotriene B4, these factors were measured in lavage fluid by radioimmunoassay. C5a was detectable in none of the normal subjects but was detectable in four of 14 BAL samples obtained from the patients. Leukotriene B4 was detectable in all subjects and was significantly elevated in the pneumonia patients (552 +/- 95 vs 81 +/- 16 pg/ml, p less than 0.01). These findings demonstrate that elevated neutrophil chemotactic activity is present in the lungs of patients with bacterial pneumonia and suggest that C5a and leukotriene B4 may account, at least in part, for this increase.

Adolescent↗
PubMedDate not supplied

Copper, zinc, and arsenic in soil surrounding Douglas-fir poles treated with ammoniacal copper zinc arsenate (ACZA).

The levels of copper, zinc, and arsenic in soil surrounding Douglas-fir [Pseudotsuga menziesii (Mirb.) Franco] utility poles treated with ammoniacal copper zinc arsenate (ACZA) were investigated at sites in Florida, Virginia, and New York. Copper levels were elevated near the poles and declined with both horizontal distance away from the pole and depth beneath the soil surface. Zinc levels were also elevated next to the poles, but the levels declined more slowly than did those of copper. Arsenic levels were elevated in soil immediately next to the poles but declined to near background levels farther away. The results indicate that metals can leach from ACZA-treated poles, but do not migrate far in the soil, and thus the levels decline sharply with distance from the poles.

Arsenates↗
PubMed2000

Kappa-opioid regulation of thymocyte IL-7 receptor and C-C chemokine receptor 2 expression.

Endogenous and exogenous kappa-opioid agonists have been widely reported to modulate the immune response. We have published results that show that the superantigen-induced proliferative response of thymocytes is inhibited by the selective kappa-opioid agonist trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrolidinyl)cyclohexyl] benzeneaceamide methanesulfonate (U50,488H). Previous work has established that the kappa-opioid receptor is widely expressed within the thymus; however, little is known about the role of the kappa-opioid receptor in the function of thymocytes. In the present report, we have examined the impact of U50,488H administration on the expression of cytokines in superantigen-stimulated thymocytes by RNase protection analysis. We have measured detectable levels of the cytokines IL-2, IL-4, IL-5, IL-13, and IFN-gamma, and the chemokines lymphotactin and RANTES, in stimulated thymocyte cultures; however, addition of U50,488H did not alter the expression of these cytokines. Examination of cytokine receptor expression by these thymocytes revealed a significant inhibition in the expression of the transcript for the IL-7 receptor alpha-chain (IL-7Ralpha), and these results were confirmed by flow cytometry. Surprisingly, the expression of several other cytokine receptor chains including the common gamma-chain, IL-2Rbeta, or the IL-2Ralpha, IL-4Ralpha, and IL-15Ralpha chains, was not altered. In contrast to these results, a significant elevation in the expression of the chemokine receptor CCR2 was observed in U50,488H-treated cultures. These results suggest that the kappa-opioid receptor may function to promote cellular migration at the expense of the sensitivity to the growth-promoting/maturation activity of IL-7.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Characterization of new pancreatic cancer-reactive monoclonal antibodies directed against purified mucin.

Although mucins have been found to be useful in the diagnosis of pancreatic cancer, the carbohydrate and peptide structures of pancreatic mucins are still not well characterized. Monoclonal antibodies were produced using mucins purified from xenografts of a human pancreatic cancer cell line as the immunogen. One of these, Ia3, reacted with almost all pancreatic, gastric, and colorectal carcinomas examined by immunoperoxidase staining, but with few normal tissues. Ia3 antigen was elevated in sera of 50.4% of individuals with gastrointestinal tumors, but its levels did not correlate with those of CA15-3, CA19-9, or DU-PAN-2. Serum Ia3 antigens migrated more slowly in sodium dodecyl sulfate-polyacrylamide gel electrophoresis than the polymorphic epithelial mucins recognized by DF3 or 115D8. Ia3 reacted only with native, and not with partially deglycosylated, pancreatic cancer xenograft mucins. Periodate or neuraminidase treatment destroyed this reactivity, but protease had little effect. The antigen recognized by another antibody, Nd2, was not detected in normal pancreatic, colonic, or gastric tissues but was present in approximately 60% of the pancreatic and gastric carcinomas examined. Nd2 reactivity with native and partially deglycosylated mucin was lost after pretreatment with protease and beta-mercaptoethanol. We conclude that, while Ia3 reacts with carbohydrates, Nd2 reactivity appears to be dependent on the integrity of the mucin protein core. The antigenic determinants of Ia3 and Nd2 are different from those of B72.3, CA19-9, DU-PAN-2, SPan-1, and several breast cancer mucin-directed antibodies. These results suggest that the malignancy-associated structures identified by Ia3 and Nd2 may provide new information on the carbohydrate and peptide structure of pancreatic cancer mucins.

Antibodies, Monoclonal↗
PubMed1981

Autoradiographic study of corneal neovascularization induced by chemical cautery.

The corneas of adult rats were cauterized chemically, and the responses of the pericorneal blood vessels and the cellular constituents of the cornea were followed by light microscopic autoradiography after labeling with 3H-thymidine. As in previous experiments, this injury elicited a neovascularization as capillaries sprouted and extended centripetally from the corneoscleral limbus to the cautery site. Chemical cautery induced a response in the epithelium, endothelium, and fibroblasts of the cornea as well as in the vascular cells. Elevated labeling indices for the corneal epithelium and endothelium began at 18 and 21 hours after injury, respectively. In all of these corneal cell types, the labeling index returned to control values by 75 hours. The onset and decline of DNA synthesis in corneal fibroblasts paralleled that of the corneal epithelium and endothelium. Labeling indices of vascular cells (endothelial cells and pericytes) increased 21 hours after injury, reached a maximal level at 45 hours, and returned to control values by 1 month after cautery. The first mitoses in vascular endothelial cells and pericytes were noted 36 hours after injury, and the initial capillary sprouts appeared at 39 hours. This study demonstrates that the thymidine incorporation by cells in the pericorneal blood vessels occurs early within the postcauterization period, at least 15 hours before the first mitotic figures are detected in these same vascular cells. The significance of the temporally related elevations in labeling indices of the vascular cells and the cellular constituents of the corneal cells is uncertain, but there are many potential interrelationships between the controls of cell division and migration for cells of the vessels, epithelium, endothelium, and corneal stroma.

Animals↗
PubMed2000

COUP-TFI (chicken ovalbumin upstream promoter-transcription factor I) regulates cell migration and axogenesis in differentiating P19 embryonal carcinoma cells.

The developmental expression patterns of the nuclear orphan receptors COUP-TFs (chicken ovalbumin upstream promoter-transcription factors) have been correlated to neurogenesis in several animal species. Nevertheless, the role of COUP-TFs in neurogenesis remains unknown. We have studied the functional involvement of COUP-TFI in retinoic acid (RA)-induced neuronal differentiation of P19 embryonal carcinoma cells through two complementary approaches: 1) deregulated expression of COUP-TFI, and 2) inactivation of endogenous COUP-TFs by means of a dominant-negative COUP-TFI mutant. Low levels of wild-type (wt)COUP-TFI transgene expression did not inhibit neural cell fate and primarily enhanced neuron outgrowth from RA-treated P19 aggregates. In contrast, high COUP-TFI expression impeded the neuronal differentiation of P19 cells induced with RA, resulting in cell cultures lacking neurons. This morphological effect was correlated to an elevated level of E-cadherin mRNA. The dominant-negative COUP-TFI mutant induced cell packing after RA treatment and inhibited neurite extension and neuron outgrowth from aggregates. A RGD peptide interference assay indicated that endogenous COUP-TFs could favor migration of neurons through an integrin-dependent mechanism. Accordingly, vitronectin mRNA levels were shown to be up-regulated by COUP-TFI by RT-PCR analysis, and COUP-TFI stimulated the mouse vitronectin promoter activity in transient transfection assays. Taken together, these data indicate that COUP-TFI is not simply a global repressor of retinoid functions, but shows a high selectivity for regulating genes involved in cellular adhesion and migration processes that are particularly important for neuronal differentiation.

Animals↗
PubMedDate not supplied

Enhanced production of macrophage inhibitory protein-1alpha in patients with Behçet's disease.

OBJECTIVE: Macrophage inhibitory protein-1alpha (MIP-1alpha), a C-C chemokine, stimulates the activation and migration of leukocytes. We investigated the expression of MIP-1alpha in patients with Behçet's disease (BD) and evaluated the association of the MIP-1alpha levels with disease activity of BD. METHODS: Serum samples were obtained from 67 BD patients and 30 healthy controls. Simultaneously, whole blood cells were isolated from BD patients (n = 25) and healthy controls (n = 11) and cultured in the absence or presence of lipopolysaccharide (LPS), phytohaemagglutinin (PHA), and phorbol 12-myristate 13-acetate (PMA) plus ionomycin. The concentrations of MIP-1alpha, interleukin-8 (IL-8), regulated on activation, normally T cell expressed and secreted (RANTES), and monocyte chemoattractant protein-1 (MCP-1) were measured in the sera and culture supernatants by enzyme-linked immunosorbent assay (ELISA). RESULTS: The serum levels of MIP-1alpha were higher in BD patients than in healthy controls. When whole blood cells were stimulated with LPS or PMA plus ionomycin, but not PHA, BD patients had higher levels of MIP-1alpha in the culture supernatants compared to healthy controls. In sera and culture supernatants of whole blood cells, MIP-1alpha levels correlated well with those of RANTES, MCP-1, and IL-8 in BD patients. Moreover, patients with active disease had significantly higher levels of serum MIP-1alpha levels compared with those with inactive disease. CONCLUSION: MIP-1alpha levels were elevated in patients with BD, and correlated well with IL-8, RANTES, and MCP-1 levels. These results suggest that the increased MIP-1alpha levels in serum of BD patients may lead to activation and migration of leukocytes, playing a role, like other chemokines, in the pathogenesis of BD.

Adult↗
PubMed1985

Evaluation of cellular immune response during chronic schistosomiasis in humans by the leukocyte aggregation test and the leukocyte migration inhibition test.

Cellular immune response was evaluated in 31 patients with chronic Schistosoma haematobium and Schistosoma mansoni infections and in 15 healthy normal persons by using S. mansoni soluble worm and egg antigens. Although the leukocyte migration inhibition test demonstrated false-positive reactions, the specificity of the leukocyte aggregation test was confirmed by the negativity of all of the controls. Among the patients, only 10% were positive for the leukocyte aggregation test. This low cellular reactivity was in contrast to markedly elevated specific humoral response determined by an enzyme-linked immunosorbent assay for immunoglobulin G and paper allergosorbent test for immunoglobulin E with soluble worm antigen. These results confirm that the cellular immune reactivity to schistosome antigen as demonstrated by the leukocyte aggregation test is either minimal or absent in chronically infected patients.

Antigens, Helminth↗
PubMed2003

Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS.

Innate responses in the CNS are critical to first line defense against infection and injury. Leukocytes migrate to inflammatory sites in response to chemokines. We studied leukocyte migration and glial chemokine expression within the denervated hippocampus in response to axonal injury caused by entorhinodentate lesions. A population of Mac1/CD11b+ CD45high macrophages (distinct from CD45low microglia) was specifically detected within the lesion-reactive hippocampus by 12 hr after injury. Significant infiltration by CD3+ T cells did not occur in the denervated hippocampus until 24 hr after axotomy. A broad spectrum of chemokines [RANTES/CCL5, monocyte chemoattractant protein (MCP)-1/CCL2, interferon gamma inducible protein (IP)-10/CXCL10, macrophage inflammatory protein (MIP)-1alpha/CCL3, MIP-1beta/CCL4, and MIP-2/CXCL2] was induced at this time. RANTES/CCL5 was not significantly elevated until 24 hr after axotomy, whereas MCP-1/CCL2 was significantly induced before leukocyte infiltration occurred. Neither T cells nor macrophages infiltrated the denervated hippocampus of CCR2-deficient mice, arguing for a critical role for the CCR2 ligand MCP-1/CCL2 in leukocyte migration. Both T cells and macrophages infiltrated CCR5-deficient hippocampi, showing that CCR5 ligands (including RANTES/CCL5) are not critical to this response. In situ hybridization combined with immunohistochemistry for ionized binding calcium adapter molecule (iba)1 or glial fibrillary acidic protein (GFAP) identified iba1+ microglia and GFAP+ astrocytes as major sources of MCP-1/CCL2 within the lesion-reactive hippocampus. We conclude that leukocyte responses to CNS axonal injury are directed via innate glial production of chemokines.

Animals↗
PubMed2003

Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor.

Characteristic of both chronic wounds and acute wounds that fail to heal are excessive leukocytosis and reduced matrix deposition. Estrogen is a major regulator of wound repair that can reverse age-related impaired wound healing in human and animal models, characterized by a dampened inflammatory response and increased matrix deposited at the wound site. Macrophage migration inhibitory factor (MIF) is a candidate proinflammatory cytokine involved in the hormonal regulation of inflammation. We demonstrate that MIF is upregulated in a distinct spatial and temporal pattern during wound healing and its expression is markedly elevated in wounds of estrogen-deficient mice as compared with intact animals. Wound-healing studies in mice rendered null for the MIF gene have demonstrated that in the absence of MIF, the excessive inflammation and delayed-healing phenotype associated with reduced estrogen is reversed. Moreover, in vitro assays have shown a striking estrogen-mediated decrease in MIF production by activated murine macrophages, a process involving the estrogen receptor. We suggest that estrogen inhibits the local inflammatory response by downregulating MIF, suggesting a specific target for future therapeutic intervention in impaired wound-healing states.

Animals↗
PubMedDate not supplied

Inhibition of Ras farnesylation by lovastatin leads to downregulation of proliferation and migration in primary cultured human glioblastoma cells.

BACKGROUND: Malignant astrocytomas are the most common primary intracranial human tumors. All therapeutic approaches are limited due to their high proliferative capacity and their ability to diffusely invade the brain. Amplification of tyrosine kinase receptors and their signaling pathways have been implicated as contributing to the molecular pathogenesis of astrocytomas, providing possible new targets for therapeutic intervention. In particular, astrocytomas, although lacking oncogenic Ras mutations, have elevated levels of activated Ras. Lovastatin, an inhibitor of the beta-hydroxy-beta-methylglutary CoA reductase (HMG-CoA-reductase), is currently used to treat patients with hypercholesterolemia. In addition, it inhibits isoprenylation of several members of the Ras superfamily of proteins and therefore has multiple cellular effects including the reduction of proliferation. MATERIALS AND METHODS: In this study, we investigated the impact of lovastatin on two human glioma cell lines and on 15 primary cell cultures established from biopsies of patients with glioblastoma multiforme (GBM,) Proliferation of glioma cell lines and primary tumor cells was determined by cell counting and by using the MTT assay. The cell morphology was analyzed by staining of actin filaments with phalloidin. Apoptosis was measured using the TUNEL assay. To investigate the influence of this drug on glioma cell motility, tumor cell migration was investigated using three dimensional spheroid disintegration assays. In addition, tumor cell invasion was analyzed with a confrontational assay between tumor spheroids and rat brain aggregates. RESULTS: Inhibition of farnesyl biosynthesis using lovastatin led to a block in Ras mediated signaling, indicated by lower MAPK activity. Consequently, tumor cell proliferation was reduced up to 80%. Lovastatin appeared to decrease glioma viability by inducing apoptosis, as indicated by morphological changes and increase of TUNEL positive cells. Lovastatin acts through isoprenoid depletion, because supplementation of the media with 50-100 microM mevalonate restored all tau eta epsilon effects. Invasion of tumor cells into brain tissue was not effected while migration was reduced beta upsilon about 30-40% in cells treated with high concentrations (> or = 100 microM) of lovastatin. This was surprising because drug treatment at lower concentrations led to a disruption of the actin cytoskeleton, as indicated by Phalloidin staining. CONCLUSION: Our data strongly suggest that inhibition of elevated Ras activity by lovastatin effectively targets the MAPK and probably other signaling pathways thus offering a pharmacological based approach for a potential treatment of human astrocytomas.

Animals↗
PubMed2001

Serum levels of soluble stem cell factor and soluble KIT are elevated in patients with atopic dermatitis and correlate with the disease severity.

BACKGROUND: Mast cell infiltration in skin lesions of atopic dermatitis (AD) is considered to play an important role in the pathogenesis of the disease. The most common factor that stimulates mast cell growth, migration and differentiation is stem cell factor (SCF), and the interaction of SCF and its receptor, KIT (tyrosine kinase transmembrane receptor), appears to be the key event in the recruitment and proliferation of mast cells. OBJECTIVES: To determine whether any altered metabolism of SCF and/or KIT is present in patients with AD. METHODS: We measured serum levels of soluble SCF (sSCF) and soluble KIT (sKIT) using enzyme-linked immunosorbent assay in 54 patients with AD, five patients with erythrodermic psoriasis vulgaris and 64 healthy individuals. RESULTS: Serum levels of both peptides in AD patients were significantly higher than those in healthy individuals, whereas patients with psoriasis vulgaris did not show any difference from healthy controls. Both sSCF and sKIT levels were positively correlated with the disease severity in AD patients, and decreased after effective treatment with topical corticosteroids. Conclusion Serum levels of sSCF and sKIT may be useful indicators for evaluation of the activity and severity of AD.

Administration, Topical↗
PubMed2002

Enhanced invasive properties exhibited by smooth muscle cells are associated with elevated production of MMP-2 in patients with aortic aneurysms.

BACKGROUND: abdominal aortic aneurysms (AAA) are associated with excessive vascular matrix remodelling. Recent findings suggest a systemic overproduction of matrix metalloproteinases-2 (MMP-2) by vascular smooth muscle cells (SMC) may be pivotal aetiologically. SMC migration is facilitated by MMP mediated proteolysis of the basement membrane and extracellular matrix. Our aim was to see if enhanced MMP-2 production by these SMC exhibit increased invasion, in an in vitro model of migration. METHOD: SMC were derived from inferior mesenteric vein (IMV) harvested from patients undergoing aneurysm repair (n=6) or colectomy for diverticulosis (n=6, control). Using a modified Boyden chamber chemotaxis was measured towards platelet derived growth factor (PDGF) and foetal calf serum (FCS) and invasion through a Matrigel layer. MMP-2 production was quantified by ELISA and gelatin zymography. RESULTS: chemoattractant studies demonstrated no difference in the effect of PDGF or FCS between the two populations of SMC. However, invasive studies demonstrated a significant increase in the number of migrating SMC isolated from IMV of AAA patients. Analysis of culture media extracts revealed that this difference was associated with a significant increase in production of MMP-2. CONCLUSION: SMC derived from patients with AAA demonstrate increased invasive properties when compared to a control group. Increased migration appears to be due to overproduction of MMP-2. The enhanced migratory potential of these SMC may lead to extracellular matrix remodelling and subsequent medial disruption demonstrated in the aneurysmal aorta. These data further support evidence of the proteolytic role of MMP-2 in cell migration.

Aortic Aneurysm, Abdominal↗