Biomedical subjects

Alan P Hudson

Publications and source records attributed to Alan P Hudson.

At least 19 recordsLinked to original sources

PubMed2006

Regulation of Sam68 activity by small heat shock protein 22.

Sam68 associates with c-Src kinase during mitosis. We previously demonstrated that Sam68 functionally replaces and/or synergizes with HIV-1 Rev in rev response element (RRE)-mediated gene expression and virus production. Furthermore, we reported that knockdown of Sam68 inhibited Rev-mediated RNA export and it is absolutely required for HIV-1 production. In the present study, we identified small heat shock protein, hsp22, as a novel interacting partner of Sam68. Hsp22 binds to Sam68 in vitro and in vivo. Overexpression of hsp22 significantly inhibits Sam68-mediated RRE- as well as CTE (constitutive transport element)-dependent reporter gene expression. Furthermore, exposing 293T cells to heat shock inhibits Sam68/RRE function by virtue of elevating hsp22. The critical domain of hsp22 that interacts with Sam68 resides between amino acids 62 and 133. Our studies provide evidence for the first time that hsp22 specifically binds to Sam68 and modulates its activity, thus playing a role in the post-transcriptional regulation of gene expression.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Molecular mimicry and horror autotoxicus: do chlamydial infections elicit autoimmunity?

All species of the order Chlamydiales are obligate intracellular eubacterial pathogens of their various hosts. Two chlamydial species, Chlamydia trachomatis and Chlamydia pneumoniae, are primarily human pathogens, and each is known to cause important diseases. Some strains of C. trachomatis are sexually transmitted and frequently cause severe reproductive problems, primarily in women. Other strains of the organism serve as the aetiological agents for blinding trachoma, still the leading cause of preventable blindness in underdeveloped nations. C. pneumoniae is a respiratory pathogen known to cause community-acquired pneumonia. Importantly, both organisms engender an immunopathogenic response in the human host, and both have been associated with widely diverse, relatively common and currently idiopathic chronic diseases, most of which include an important autoimmune component. In this article, we explore the available experimental data regarding the possible elicitation of autoimmunity in various contexts by chlamydial infection, and we suggest several avenues for research to explore this potentially important issue further.

Animals↗

PubMed2006

Chlamydophila (Chlamydia) pneumoniae in the Alzheimer's brain.

We assessed the presence and characteristics of the intracellular pathogen Chlamydophila (Chlamydia) pneumoniae in brain-tissue samples from 25 patients with late-onset Alzheimer's disease (AD) and 27 non-AD control individuals. 20/27 AD patients, but only 3/27 controls, were PCR-positive in multiple assays targetting the Cpn1046 and Cpn0695 genes. Culture of the organism from brain-tissue homogenate from one AD patient, and assessment of various chlamydial transcripts in RNA preparations from several patients, demonstrated that the organisms were viable and metabolically active in those samples. Immunohistochemical analyses showed that astrocytes, microglia, and neurons all served as host cells for C. pneumoniae in the AD brain, and that infected cells were found in close proximity to both neuritic senile plaques and neurofibrillary tangles in the AD brain. These observations confirm and significantly extend our earlier study suggesting that this unusual pathogen may play a role in the neuropathogenesis characteristic of AD.

Aged↗

PubMed2006

Transcriptome profiling of Saccharomyces cerevisiae during a transition from fermentative to glycerol-based respiratory growth reveals extensive metabolic and structural remodeling.

Transcriptome analyses using a wild-type strain of Saccharomyces cerevisiae were performed to assess the overall pattern of gene expression during the transition from glucose-based fermentative to glycerol-based respiratory growth. These experiments revealed a complex suite of metabolic and structural changes associated with the adaptation process. Alterations in gene expression leading to remodeling of various membrane transport systems and the cortical actin cytoskeleton were observed. Transition to respiratory growth was accompanied by alterations in transcript patterns demonstrating not only a general stress response, as seen in earlier studies, but also the oxidative and osmotic stress responses. In some contrast to earlier studies, these experiments identified modulation of expression for many genes specifying transcription factors during the transition to glycerol-based growth. Importantly and unexpectedly, an ordered series of changes was seen in transcript levels from genes encoding components of the TFIID, SAGA (Spt-Ada-Gcn5-Acetyltransferase), and SLIK (Saga LIKe) complexes and all three RNA polymerases, suggesting a modulation of structure for the basal transcriptional machinery during adaptation to respiratory growth. In concert with data given in earlier studies, the results presented here highlight important aspects of metabolic and other adaptations to respiratory growth in yeast that are common to utilization of multiple carbon sources. Importantly, they also identify aspects specific to adaptation of this organism to growth on glycerol as sole carbon source.

Adaptation, Physiological↗

PubMed2006

Fate of Chlamydophila pneumoniae in human monocyte-derived dendritic cells: long lasting infection.

Earlier studies from this group demonstrated that Chlamydophila pneumoniae co-localized with dendritic cells (DC) in temporal artery biopsies from patients with giant cell arteritis (GCA). To investigate the interaction of DC with C. pneumoniae we employed an in vitro cell culture system of human monocyte derived DC. These DC were infected with C. pneumoniae and observed at regular time intervals up to 25 days post infection. Chlamydiae were visualized inside DC by both confocal and electron microscopy. Statistical analysis showed an increase in the number of chlamydial antigen during that period (p < 0.00005, chi2-test). Titration of DC lysates on HEp-2 cells showed that infectious progeny was recovered at various intervals but showed no exponential growth. Additionally, RT-PCR analyses of infected DC identified transcripts from dnaA, ftsK and tal throughout a period of 14 days, indicating viable chlamydiae. Thus, human monocyte-derived DC are susceptible to C. pneumoniae infection. These results indicate that C. pneumoniae-infected DC can play an important role in the transmission of these bacteria in GCA and other chlamydial diseases.

Antigens, Bacterial↗

PubMed2006

Chlamydophila (Chlamydia) pneumoniae infection of human astrocytes and microglia in culture displays an active, rather than a persistent, phenotype.

BACKGROUND: The intracellular pathogen Chlamydia pneumoniae can cause persistent infections during which its morphologic, molecular, and pathogenic characteristics differ importantly from those of active infection. This bacterium was identified within astrocytes and microglia in the brain of late-onset Alzheimer disease patients. We investigated whether infection of these two host cell types displays an active or persistent growth phenotype. METHODS: The human astrocytoma and microglioma cell lines U-87 MG and CHME-5 (respectively) and the human epithelial cell line HEp-2 were infected by the standard method with C pneumoniae strain AR-39. Cultures were harvested at 24, 48, and 72 hours postinfection and subjected to analysis of inclusion morphology. DNA and RNA were prepared from portions of each infected culture sample and analyzed for relative chromosome accumulation and presence or absence of several specific bacterial mRNAs. RESULTS: Astrocytes and microglial cells infected in vitro with C pneumoniae displayed inclusions that were indistinguishable from those characteristic of active infection of the standard HEp-2 host cell line. Real time polymerase chain reaction (PCR) showed that the relative accumulation of chlamydial chromosome over time during infection of these two cell lines also was virtually identical to that in actively infected HEp-2 cells. Reverse transcriptase PCR (RT-PCR) analyses showed that mRNA from ftsK, pyk, and other chlamydial genes whose expression is abrogated during persistent infection were easily identifiable in infected CHME-5 and U-87 MG cells. CONCLUSIONS: In cultured human astrocytes and microglia, C pneumoniae displays an active, not a persistent, growth phenotype. This indicates normal passage through the developmental cycle with its probable concomitant destruction by lysis of some portion of host cells at the termination of that cycle.

Astrocytes↗

PubMed2005

The YJR127C/ZMS1 gene product is involved in glycerol-based respiratory growth of the yeast Saccharomyces cerevisiae.

A putative yeast mitochondrial upstream activating sequence (UAS) was used in a one-hybrid screening procedure that identified the YJR127C ORF on chromosome X. This gene was previously designated ZMS1 and is listed as a transcription factor on the SGD website. Real time RT-PCR assays showed that expression of YJR127C/ZMS1 was glucose-repressible, and a deletion mutant for the gene showed a growth defect on glycerol-based but not on glucose- or ethanol-based medium. Real time RT-PCR analyses identified severely attenuated transcript levels from GUT1 and GUT2 to be the source of that growth defect, the products of GUT1 and GUT2 are required for glycerol utilization. mRNA levels from a large group of mitochondria- and respiration-related nuclear genes also were shown to be attenuated in the deletion mutant. Importantly, transcript levels from the mitochondrial OLI1 gene, which has an associated organellar UAS, were attenuated in the DeltaYJR127C mutant during glycerol-based growth, but those from COX3 (OXI2), which lacks an associated mitochondrial UAS, were not. Transcriptome analysis of the glycerol-grown deletion mutant showed that genes in several metabolic and other categories are affected by loss of this gene product, including protein transport, signal transduction, and others. Thus, the product of YJR127C/ZMS1 is involved in transcriptional control for genes in both cellular genetic compartments, many of which specify products required for glycerol-based growth, respiration, and other functions.

Cell Respiration↗

PubMed2005

Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice.

Schistosomiasis mansoni, a tropical helminthic disease, is caused by disseminated worm eggs that induce CD4(+) T-cell mediated granulomatous inflammation and fibrosis. T suppressor cell activity has been proposed as one of the mechanisms active in the down-modulation of the murine disease during the chronic stage (16-20 weeks of the infection). In recent years a new category of the CD4(+) CD25(+) T regulatory (Treg) lymphocyte has been identified that maintains immune tolerance to self, and also functions in the regulation of parasite-induced immunopathology. The Foxp3 gene which encodes the transcription factor Scurfin was found to be expressed by and required for the generation of CD4(+) CD25(+) T reg. At 8 weeks of the infection Foxp3 gene expression of splenocytes was similar to that of naive mice, but increased fourfold by 16 weeks. In contrast, granulomatous livers at 8 and 16 weeks showed 10- and 30-fold increases, respectively, in gene expression compared with normal liver. The percentage of granuloma CD4(+) CD25(+) T cells rose from 12% at 8 weeks to 88% at 16 weeks of the infection. Foxp3 expression was 3.5-fold higher in the CD4(+) CD25(+) versus the CD4(+) CD25(-) T cells in the 8 week infection granulomas. As a novel observation neuropilin-1 membrane expression, a recently identified marker for Treg, was correlated with Foxp3 expression in the granuloma CD4(+) CD25(+) but not the CD25(-) cells. Co-incubation with polyclonal stimulation of CD4(+) CD25(+) splenic cells with CD4(+) CD25(-) cells suppressed proliferation of the latter. Retroviral transfer of the Foxp3 gene at the onset of granuloma formation enhanced fourfold Foxp3 expression in the granuloma CD4(+) CD25(+) T cells and strongly suppressed full granuloma development. Gene transfer also significantly enhanced transforming growth factor-beta, interferon-gamma and interleukin-4 but not interleukin-10 expression. It is concluded, that CD4(+) CD25(+), Foxp3(+) Treg cells also regulate schistosome egg-induced immunopathology.

Animals↗

PubMed2004

Differential expression of three Chlamydia trachomatis hsp60-encoding genes in active vs. persistent infections.

Real time RT-PCR was used to assess expression of the three Chlamydia trachomatis hsp60-encoding genes (Ct110, Ct604, Ct755) over time in in vitro systems of active vs. persistent infection, and in synovial samples from patients with Chlamydia-induced arthritis. In HEp-2 cells actively infected with C. trachomatis (serovar K), mRNA from Ct110 (groEL) was apparent by 8 h post-infection (p.i.) and increased more than 10-fold through 48 h p.i.; mRNA from Ct604 followed a similar pattern. Transcripts from Ct755 were abundant at 8 h p.i. and remained 2-3-fold higher than those from Ct110 at all times. In persistently infected human monocytes in culture, expression of Ct110 and Ct755 was low from 1 to 7d p.i., while mRNA from Ct604 was abundant at 1d p.i. and increased more than 3-fold from 1 to 3d p.i., as the organism transited to the persistent state. Those mRNA levels remained high through 7d p.i. Real time analyses of RNA/cDNA from synovial tissue of patients with Chlamydia-associated arthritis showed high Ct604 mRNA levels, consistent with results from the in vitro monocyte system of persistence. These data demonstrate that each chlamydial hsp60-encoding gene is expressed independently, and that the three genes are expressed differentially in active vs. persistent infection. The results further suggest that the Ct604 gene product may function importantly during chlamydial persistence.

Adult↗

PubMed2004

The molecular genetic basis of mitochondrial malfunction in bladder tissue following outlet obstruction.

PURPOSE: Bladder dysfunction following partial outlet obstruction is a frequent consequence of benign prostatic hyperplasia and an increasingly common problem given the aging of the general population. Recent studies from this and other groups have begun to elucidate the molecular bases for the well described physiological malfunctions that characterize this clinical entity. We summarized and synthesized that information. MATERIALS AND METHODS: Using modern methods of molecular genetics, including real-time polymerase chain reaction, real-time reverse transcriptase-polymerase chain reaction and others, as well as traditional experimental techniques such as electron microscopy we and others examined the transcriptional profile, morphology, etc of bladder smooth muscle mitochondria in experimental models of outlet obstruction. RESULTS: Data from many studies have demonstrated that aberrant gene expression in the mitochondrial and mitochondria related nuclear genetic systems underlies the loss of compliance and other attributes of bladder dysfunction following outlet obstruction. Such aberrant transcriptional characteristics engender loss of function in the electron transport and oxidative phosphorylation systems. Morphological studies of mitochondria in the animal model systems support this conclusion. CONCLUSIONS: In large part the loss of function in bladder smooth muscle following outlet obstruction results from the attenuation of mitochondrial energy production. In this article we reviewed and synthesized all available experimental observations relevant to this problem and we suggest future lines of inquiry that should prove fruitful in developing new strategies to treat the condition.

Animals↗

PubMed2004

Expression of matrix metalloproteinases and their inhibitors during the resorption of schistosome egg-induced fibrosis in praziquantel-treated mice.

Schistosomiasis mansoni is a tropical helminthic disease characterized by parasite egg-induced granulomatous inflammation and cumulative fibrosis. Because fibrosis is influenced by the imbalance between degradative matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), we analysed the resorption of fibrous tissue and MMP/TIMP expression in the livers of S. mansoni-infected and praziquantel-cured mice. Worm elimination significantly enhanced survival rate, ameliorated the granulomatous pathology and reduced collagen I, III and IV gene expression at 6 and 12 months post-treatment. Compared to 6 months infected, untreated controls, liver fibrous tissue was resorbed by 71.4% at 12 months after treatment. At 3 months post-treatment, expression of the MMP-2, -3, -8, -10, -13, -14 and -16 genes decreased compared with untreated controls. By 6 months, a highly significant increase in MMP-10 gene expression was manifest. At 12 months, messages for all MMP genes decreased in relation to untreated controls. TIMP-1, -2 and -3 gene expression drastically decreased between 3 and 6 months. At 1 year, only TIMP-1 expression was significantly diminished. Overall, profibrogenic tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta and inducible nitric oxide synthase (iNOS) gene expression decreased. Antigen-stimulated splenocytes secreted significantly higher levels of interleukin (IL)-4, IL-5, IL-10 and IL-13 cytokines between 3 and 12 months after treatment. Production of interferon (IFN)-gamma was higher than in untreated controls 3 and 6 months after treatment. In conclusion, praziquantel-treated mice showed a slow resorption of liver fibrous tissue. Resorption is attributed to the precipitous drop in TIMP-1 gene expression level, which shifted the balance in favour of MMP message expression and presumed enhanced collagenase activity.

Animals↗

PubMed2004

Chemokines in autoimmune lacrimal gland disease in MRL/MpJ mice.

PURPOSE: MRL/MpJ-fas+/fas+ (MRL/+) and MRL/MpJ-fas(lpr)/fas(lpr) (MRL/lpr) mice undergo spontaneous development of inflammation of the lacrimal and salivary glands, similar to that in the human disorder Sjögren's syndrome. Previous work has shown that these lesions appear to be largely T helper (Th)-2-driven, as evidenced by the substantially greater expression of IL-4 than interferon-gamma. The relative contributions of selected chemokines associated with Th1 and Th2 immune responses were assessed. METHODS: Lacrimal glands from MRL/+ and MRL/lpr mice, at ages 1.5 through 9 months were evaluated by immunohistochemistry for the chemokines monocyte chemoattractant protein (MCP)-1 (also known as chemokine ligand [CCL]-2), MCP-5 (CCL12), thymus activation regulated chemokine (TARC; or CCL17), and macrophage-derived chemokine (MDC; or CCL22). Additional lacrimal glands were tested by real-time RT-PCR for chemokines MCP-1 and -5, which are associated with Th2 and Th1 responses, respectively. RESULTS: By immunohistochemistry a significantly greater proportion of mononuclear inflammatory cells in the lacrimal gland lesions stained for MCP-1 (29%-48% depending on age) compared with MCP-5 (1%-3% depending on age) both in MRL/+ (mean difference 34.2%, P < 0.001) and MRL/lpr (mean difference 33.6%, P < 0.001) substrains. Real-time RT-PCR studies showed higher transcript levels of MCP-1 compared with MCP-5, in both MRL/+ (median difference, 37.3; P < 0.0001) and MRL/lpr (median difference, 77.1; P < 0.0001) mice. Relative transcripts of MCP-1 increased with age in both MRL/+ mice (P = 0.02) and MRL/lpr mice (P = 0.03). Staining for TARC was present on lacrimal gland ductular cells but not on the infiltrating lymphocytes, and staining for MDC was present on scattered individual cells throughout the lacrimal gland, but not on infiltrating lymphocytes. CONCLUSIONS: The predominant expression of a Th2-associated chemokine in the lacrimal gland lesions in this murine model of Sjögren's syndrome may contribute to the predominantly Th2-type lymphoid infiltrate in these tissues.

Animals↗

PubMed2004

Inflammatory mediators in autoimmune lacrimal gland disease in MRL/Mpj mice.

PURPOSE: MRL/MpJ-fas(+)/fas(+) (MRL/+) and MRL/MpJ-fas(lpr)/fas(lpr) (MRL/lpr) mice are congenic substrains of mice that have spontaneously developing lacrimal and salivary gland inflammation and are models for the human disorder Sjögren's syndrome. Nitric oxide (NO) and tumor necrosis factor (TNF)-alpha are proinflammatory and potential mediators of tissue damage. The presence of the inducible form of nitric oxide synthase (iNOS), which catalyzes the production of NO, and the presence TNF-alpha in the lacrimal glands of MRL/MpJ mice were assessed. METHODS: Lacrimal glands from MRL/+ and MRL/lpr mice, at ages 1 through 9 months, were evaluated by real-time RT-PCR for iNOS and TNF-alpha mRNA and by immunohistochemistry for the presence of iNOS and of TNF-alpha. Age-matched BALB/c lacrimal glands were used as the control. RESULTS: By quantitative real-time PCR (qPCR), mRNA for iNOS was detected in the lacrimal glands in significantly greater amounts in both MRL/+ (median, normalized to 18S rRNA, 2.90; P < 0.0003) and MRL/lpr mice (median 6.84, P < 0.001) than in BALB/c mice (median 0.34). By qPCR, mRNA for TNF-alpha in the lacrimal glands was detected in significantly greater amounts in aged MRL/+ mice than in BALB/c mice (median, normalized to actin, 221.8 vs. 77.8, P = 0.011) and in MRL/lpr mice than in BALB/c mice (median 136.7 vs. 72.5, P = 0.001). Immunohistochemistry demonstrated both iNOS and TNF-alpha in scattered mononuclear cells throughout the lacrimal glands and in mononuclear cells at the junction of the focal inflammatory infiltrates and normal acinar tissue in both MRL/+ and MRL/lpr mice. CONCLUSIONS: As demonstrated by the greater presence of iNOS and TNF-alpha in the lacrimal glands of MRL/MpJ mice than in control glands, both NO and TNF-alpha are potential mediators of lacrimal gland damage in these murine models of Sjögren's syndrome.

Animals↗

PubMed2003

Rsf1p, a protein required for respiratory growth of Saccharomyces cerevisiae.

A central problem in our understanding of mitochondrial (mt) function remains the question of how coordinate transcriptional control is accomplished between nucleus and mitochondria. Here, we report the initial characterization of a protein of previously unknown function, the product of the YMR030 W gene, that appears to mediate such coordinate gene expression. Expression of YMR030 W is glucose-repressible; a deletion mutant for this gene shows a severe growth defect on glycerol-, but not glucose- or ethanol-based medium. In that mutant, transcript levels from GUT1 and GUT2 are highly attenuated compared with those of the wild-type parent when both are grown on glycerol-based medium. Under the same growth conditions, transcripts from the mt OLI1 gene, which has one copy of a mt upstream activating sequence (UAS) in its 5'-flanking region, are attenuated in the DeltaYMR030 W mutant, but mRNA from the mt COX3 ( OXI2) gene, which lacks the mt UAS, are not. Some nuclear genes encoding mt-related proteins also show low transcript levels in the DeltaYMR030 W mutant in comparison with those of the wild-type parent strain during glycerol-based growth. Localization of the protein, via its expression fused to green fluorescent protein, indicates that it is present in both nucleus and mitochondria, supporting a respiration-related transcriptional role for this gene product in both cellular genetic compartments. Because of its role in both respiratory growth and mt function, we designate the YMR030 W coding sequence RSF1 (respiration factor 1).

Cell Nucleus↗

PubMed2003

Infectious agents and multiple sclerosis--are Chlamydia pneumoniae and human herpes virus 6 involved?

A good deal of evidence suggests an infectious component in the development of multiple sclerosis (MS) and, to date, some 20 bacteria and viruses have been associated with the disease. Recent independent sets of studies have implicated the respiratory bacterium Chlamydia pneumoniae and human herpes virus 6 (HHV-6) in the pathogenesis of MS. However, as is the case for essentially all earlier microbial associations, experimental evidence linking either this bacterium or this virus to MS is equivocal. We review the published reports concerning involvement of C. pneumoniae and HHV-6 in MS, and data relating to possession of the APOE epsilon 4 allele, which some studies indicate might influence how these or other pathogens affect disease genesis. Based on the large set of inconsistent observations available and given important new information regarding the neuropathology of MS, we contend that no conclusion is possible at this point regarding the potential role of either C. pneumoniae or HHV-6 in MS. We therefore propose future studies that should clarify whether, and if so how, these and other organisms function in the pathogenesis of this disease.

Apolipoprotein E4↗

PubMed2003

Detection of nucleotide variability in rpoB in both rifampin-sensitive and rifampin-resistant strains of Chlamydia trachomatis.

A 656-bp PCR fragment from rpoB was sequenced from five rifampin-resistant Chlamydia trachomatis variants selected in vitro from a wild-type parent with a surprising level of genetic variability in this region. Three variants (MIC, 4 microg/ml) showed Ala522-->Val in cluster I (codons 507 to 533), which harbors mutations in most rifampin-resistant bacteria. Two high-level resistance variants (MICs, 64 and 256 microg/ml) showed His526-->Tyr in cluster I with additional genetic variation, some of which resulted in amino acid substitutions. None of the latter was situated in clusters related to rifampin resistance in other bacteria.

Antibiotics, Antitubercular↗

PubMed2002

Cloning of COX4 cDNA from the NZ white rabbit and expression of this gene in bladder smooth muscle following partial outlet obstruction.

We cloned and characterized the rabbit COX4 coding sequence, then examined expression of the gene in bladder smooth muscle following partial obstruction of the bladder outlet. Obstruction was done surgically in male NZ white rabbits and bladders procured at 1, 3, 5, 7, and 14 days post-obstruction (two animals/time). RNA, then cDNA, was prepared from smooth muscle from each sample. Cloning was done from cDNA by PCR. COX4 mRNA in smooth muscle was defined by real-time RT-PCR, using cDNA from bladder samples. The rabbit COX4 coding sequence specifies a protein of 169 amino acids, including a membrane transit sequence for mitochondrial (mt) entry. Expression of COX4 in bladder smooth muscle decreased by 80% in the first day post-obstruction and remained low through 14 days post-obstruction. Cytochrome oxidase activity decreased sharply in the first 3 days post-obstruction in smooth muscle, in concert with COX4 transcript levels. Partial outlet obstruction of the rabbit urinary bladder results in attenuation in smooth muscle of mRNA synthesis from the COX4 gene. In turn, this results in attenuated activity of mt electron transport due to limited availability of nucleus-encoded components required for the assembly of cytochrome oxidase.

Animals↗

PubMed2002

Soluble egg antigens from Schistosoma mansoni induce angiogenesis-related processes by up-regulating vascular endothelial growth factor in human endothelial cells.

Schistosomiasis mansoni is characterized by hepatic granuloma formation. Endothelial cell activation within these granulomas may contribute to their development and to increased vascularization in the granuloma periphery. The earliest event in granuloma formation is the lodging of schistosome eggs within presinusoidal capillaries. The eggs secrete factors that may activate endothelial cells. This study investigated the effects of Schistosoma mansoni soluble egg antigen (SEA) on angiogenic processes: proliferation, tube formation, and apoptosis of human umbilical vein endothelial cells (HUVECs). HUVECs require serum and growth factors to proliferate in vitro. Proliferation occurred when SEA or live eggs were substituted for growth factors, but not for serum. SEA increased HUVEC tube formation and decreased HUVEC apoptosis after serum and growth factor deprivation. Messenger RNA for vascular endothelial growth factor (VEGF) increased 2-fold in SEA-treated HUVECs. These findings suggest that products secreted by schistosome eggs may promote angiogenesis within hepatic granulomas by up-regulating endothelial cell VEGF.

Animals↗