Biomedical subjects

C Faber

Publications and source records attributed to C Faber.

At least 19 recordsLinked to original sources

PubMed2006

Differential expression patterns of recombination-activating genes in individual mature B cells in juvenile idiopathic arthritis.

BACKGROUND: Re-expression of the recombination-activating genes (RAG) in peripheral B cells may be relevant in the development of autoreactive antibodies in autoimmune diseases. The presence of antinuclear antibodies (ANA) as a hallmark of oligoarticular juvenile idiopathic arthritis (o-JIA, early-onset type) indicates a breakdown in immunological tolerance. AIM: To examine the expression of RAG genes in peripheral blood mature B lymphocytes in patients with o-JIA. METHODS: 777 memory B cells from peripheral blood, CD19+ CD27+ CD5+ or CD19+ CD27+ CD5-, isolated from three ANA+ children with o-JIA and three healthy age-matched children, were examined for the expression of RAG1 and RAG2 mRNA. mRNA transcripts of activation-induced cytidine deaminase and immunoglobulin G were searched to further determine their developmental stage. RESULTS: mRNA was present for any of the two RAG genes in the B cells of children with JIA and controls. However, the predominance of RAG1 or RAG2 was different. A significantly decreased frequency of RAG2-expressing memory B cells in both CD5+ and CD5- populations was noted in children with JIA (p<0.001), whereas the number of RAG1-expressing B cells was slightly increased. The coordinate expression of both the RAG genes was a rare event, similar in the CD5+ populations (1% in controls, 2% in children with JIA), but different among the CD5- compartments (5% v 0%; p<0.01). CONCLUSION: These results argue for a reduced coordinate RAG expression in the peripheral CD5- memory B cells of patients with o-JIA. Thus, it was hypothesised that impaired receptor revision contributes to autoimmune pathogenesis in JIA.

Arthritis, Juvenile↗

PubMed2006

In vivo high-resolution MR imaging of neuropathologic changes in the injured rat spinal cord.

BACKGROUND AND PURPOSE: MR imaging is the most comprehensive noninvasive means to assess structural changes in injured central nervous system (CNS) tissue in humans over time. The few published in vivo MR imaging studies of spinal cord injury in rodent models by using field strengths < or = 7T suffer from low spatial resolution, flow, and motion artifacts. The aim of this study was to assess the capacity of a 17.6T imaging system to detect pathologic changes occurring in a rat spinal cord contusion injury model ex vivo and in vivo. METHODS: Seven adult female Fischer 344 rats received contusion injuries at thoracic level T10, which caused severe and reproducible lesions of the injured spinal cord parenchyma. Two to 58 days postinjury, high-resolution MR imaging was performed ex vivo (2) or in vivo in anesthetized rats (5 spinal cord injured + one intact control animal) by using 2D multisection spin- and gradient-echo imaging sequences, respectively, combined with electrocardiogram triggering and respiratory gating. RESULTS: The acquired images provided excellent resolution and gray/white matter differentiation without significant artifacts. Signal intensity changes, which were detected with ex vivo and in vivo MR imaging following spinal cord injury, could be correlated with histologically defined structural changes such as edema, fibroglial scar, and hemorrhage. CONCLUSIONS: These results demonstrate that MR imaging at 17.6T allows high-resolution structural analysis of spinal cord pathology after injury.

Animals↗

PubMed2005

Analysis of RAG expression by peripheral blood CD5+ and CD5- B cells of patients with childhood systemic lupus erythematosus.

BACKGROUND: The assembly of immunoglobulin genes during B cell development in the bone marrow is dependent on the expression of recombination activating genes (RAG) 1 and 2. Recently, RAG expression in peripheral blood IgD+ B cells outside the bone marrow has been demonstrated and is associated with the development of autoimmune diseases. OBJECTIVE: To investigate RAG expression in the CD5+ or CD5- IgD+ B cell compartment in childhood systemic lupus erythematosus (SLE). METHODS: Using a combination of flow cytometric cell sorting and reverse transcriptase polymerase chain reaction analysis of cDNA libraries generated from individual cells, the expression of RAG, VpreB, and CD154 mRNA by individual peripheral blood B cells of three paediatric SLE patients was examined in detail. RESULTS: While only one patient had a significantly increased frequency of RAG+ B cells in the CD5- B cell population, all patients showed higher frequencies of RAG+ B cells in the CD5+IgD+ B cell population. The frequency of RAG+ IgD+CD5+/- B cells was reduced during intravenous cyclophosphamide treatment. In healthy age matched children, RAG expressing IgD+ B cells were hardly detectable. Coexpression of RAG and VpreB or CD154 mRNA could only be found in SLE B cells. CONCLUSIONS: RAG expression in peripheral blood B cells of SLE patients is particularly increased in the IgD+CD5+ B cell population. CD5+ and CD5- B cells in SLE have the potential to undergo receptor revision leading to the generation of high affinity pathogenic autoantibodies.

Adolescent↗

PubMed2005

The effect of the antimicrobial peptide, Dhvar-5, on gentamicin release from a polymethyl methacrylate bone cement.

The objective of this study was to investigate the release mechanism and kinetics of the antimicrobial peptide, Dhvar-5, both alone and in combination with gentamicin, from a standard commercial polymethyl methacrylate (PMMA) bone cement. Different amounts of Dhvar-5 were mixed with the bone cement powders of Osteopal and the gentamicin-containing Osteopal G bone cement and their release kinetics from the polymerized cement were investigated. Additionally, the internal structure of the bone cements were analysed by scanning electron microscopy (SEM) of the fracture surfaces. Secondly, porosity was investigated with the mercury intrusion method and related to the observed release profiles. In order to obtain an insight into the mechanical characteristics of the bone cement mixtures, the compressive strength of Osteopal and Osteopal G with Dhvar-5 was also investigated. The total Dhvar-5 release reached 96% in the 100 mg Dhvar-5/g Osteopal cement, whereas total gentamicin release from Osteopal G reached only 18%. Total gentamicin release increased significantly to 67% with the addition of 50mg Dhvar-5/g, but the Dhvar-5 release was not influenced. SEM showed an increase of dissolved gentamicin crystals with the addition of Dhvar-5. The mercury intrusion results suggested an increase of small pores (< 0.1 microm) with the addition of Dhvar-5. Compressive strength of Osteopal was reduced by the addition of Dhvar-5 and gentamicin, but still remained above the limit prescribed by the ISO standard for clinical bone cements. We therefore conclude that the antimicrobial peptide, Dhvar-5, was released in high amounts from PMMA bone cement. When used together with gentamicin sulphate, Dhvar-5 made the gentamicin crystals accessible for the release medium presumably through increased micro-porosity (< 0.1 microm) resulting in a fourfold increase of gentamicin release.

Antimicrobial Cationic Peptides↗

PubMed2004

23Na microscopy of the mouse heart in vivo using density-weighted chemical shift imaging.

The mouse has become an important animal model for human cardiac disease, and the development of techniques for non-invasive imaging of the mouse heart in vivo is, therefore, of great potential interest. Previous magnetic resonance imaging studies have concentrated on pathologically induced changes in cardiac structure and dynamics by acquiring proton images. Further information can be gained by studying cardiac function and physiology using other nuclei, for example, sodium. Sodium imaging of such a small structure presents considerable technical challenges. In this work we show the first sodium images of the mouse heart, with an isotropic spatial resolution of 1 x 1 x 1 mm, acquired in a time of 1.5 h. The ventricles, septum and myocardium are readily distinguishable in these images, which were acquired through the combination of 3D density-weighted chemical shift imaging, optimized instrumentation, and a high magnetic field strength (17.6 T). Measurements of the myocardial:blood sodium concentration in the left and right ventricles agree well with theoretical values.

Animals↗

PubMed2004

High-resolution MR imaging of the rat spinal cord in vivo in a wide-bore magnet at 17.6 Tesla.

The objective was to demonstrate the feasibility and to evaluate the performance of high-resolution in vivo magnetic resonance (MR) imaging of the rat spinal cord in a 17.6-T vertical wide-bore magnet. A probehead consisting of a surface coil that offers enlarged sample volume suitable for rats up to a weight of 220 g was designed. ECG triggered and respiratory-gated gradient echo experiments were performed on a Bruker Avance 750 wide-bore spectrometer for high-resolution imaging. With T*2 values between 5 and 20 ms, good image contrast could be obtained using short echo times, which also minimizes motion artifacts. Anatomy of healthy spinal cords and pathomorphological changes in traumatically injured rat spinal cord in vivo could be visualized with microscopic detail. It was demonstrated that imaging of the rat spinal cord in vivo using a vertical wide-bore high-magnetic-field system is feasible. The potential to obtain high-resolution images in short scan times renders high-field imaging a powerful diagnostic tool.

Animals↗

PubMed2004

Differential expression of matrix metalloproteinases and cyclooxygenases in synovial cells exposed to Borrelia burgdorferi.

OBJECTIVE AND DESIGN: Lyme arthritis is characterized by strong inflammatory reactions probably due to the presence of Borrelia burgdorferi in the joint. It has been suggested that Borrelia adopts different molecular mechanisms that either can amplify the host's inflammatory response or can suppress it. In the present study we analyzed the induction of matrix metalloproteinases (MMPs) and cyclooxygenases (COXs) in human synoviocytes exposed to different B. burgdorferi sensu stricto isolates (Geho and B31). MATERIALS AND METHODS: Synoviocytes were exposed in vitro for 12 h up to 5 days. Semiquantitative reverse transcription polymerase chain reaction was used to assess the mRNA expression of MMP-1 to 13, COX-1 and COX-2. Prostaglandin E2 (PGE2) production was assessed by ELISA. RESULTS: MMP-1 was unchanged in synovial cells exposed to strain Geho, whereas it was downregulated by strain B31. MMP-13 was downregulated by both strains. COX-2 was upregulated by strain B31, which resulted in increased PGE2 concentration in the supernatant. In contrast, COX-1 was slightly upregulated and COX-2 tended to be downregulated by Geho resulting in a decreased PGE2 concentration. CONCLUSIONS: The differential expression of MMPs and COXs suggests that different B. burgdorferi strains influence different molecular mechanisms leading to chronic inflammation. This might be reflected in the clinical variability among Lyme arthritis patients.

Borrelia burgdorferi↗

PubMed2004

Zinc in pharmacological doses suppresses allogeneic reaction without affecting the antigenic response.

Zinc is an essential trace element for the immune system. Previously it was shown that zinc inhibits alloreactivity. In our present in vitro experiments, it is shown that zinc maintains the antigenic potency of the host while blocking the allogeneic response. These results were observed in experiments using tetanus toxoid as a well-established recall antigen and the mixed lymphocyte culture as an in vitro model for allogeneic reaction. To prove the in vivo relevance, an ex vivo experimental setup was established. This involved participants taking zinc orally for 1 week. Here it is shown that in vivo zinc application induced the same effect of blocking the mixed lymphocyte culture without influencing tetanus toxoid stimulation. So far, no clinical application studies have been performed, but the observed selective suppression of allogeneic reaction by zinc is the first step towards a new generation of immunosuppressants.

Cells, Cultured↗

PubMed2003

Release of antimicrobial peptide Dhvar-5 from polymethylmethacrylate beads.

Osteomyelitis is still a major cause of morbidity and remains a difficult complication to treat in orthopaedic surgery. The treatment of choice is a combination of systemic and local antibiotics. The insertion of gentamicin-loaded polymethylmethacrylate (PMMA) beads into the bone results in high local concentrations of gentamicin and low systemic concentrations. However, the effectiveness of this treatment is being hampered by the emergence of antimicrobial resistance. New antimicrobial agents are therefore needed. One new class of promising antibiotics is antimicrobial peptides (AMP). Derived from natural human peptides, these have a low tendency to induce antimicrobial resistance. Dhvar-5 is an antimicrobial peptide based on histatin-5, which is found in human saliva and consists of 14 amino acids. It has demonstrated bactericidal activity in vitro. In order to develop a new local treatment using Dhvar-5 for osteomyelitis, we investigated its release from PMMA beads and its antimicrobial activity against a clinical isolate of methicillin-resistant Staphylococcus aureus (MRSA) before and after release from PMMA beads. Specific amounts of Dhvar-5 were incorporated into PMMA mini beads, containing 120, 600 and 1200 microg of Dhvar-5, respectively. Dhvar-5 was released from the beads in all three groups. Total release from the 120 microg beads was 9 microg per bead after 7 days. However, the release per bead in the 600 and 1200 microg beads was far more, respectively, 416 and 1091 microg over a 28 day period. After release, the Dhvar-5 also retained its antimicrobial activity against MRSA. On the basis of these data we conclude that the amount of Dhvar-5 release from PMMA beads is not proportionate to the amount incorporated; instead, it demonstrated an exponential relationship to the amount of total peptide released. Furthermore, the released peptide remained biologically active against a clinical isolate of MRSA.

Anti-Bacterial Agents↗

PubMed2003

Review of laparoscopic and open colorectal surgery in the "Zitha" Hospital (Luxembourg) in the year 2002.

BACKGROUND: A review and outcome of laparoscopic colorectal surgery in the visceral surgery unit in the Zitha Hospital for the year 2002. METHODS: All patients, presenting with benign or malignant disease of the colon or rectum were evaluated. Depending on the tumour size, a laparoscopic approach is advocated whenever possible. Operation and patient specific factors (age, duration of the procedure and duration of hospital stay, diagnosis of malignant tumour versus benign disease, conversion and complication rate) are presented. Patients who had to be converted are classified under the open surgery group. RESULTS: A total of 103 laparoscopic or open procedures on the colon/rectum were performed between the 1st of January 2002 and the 31st of December 2002. 74% were treated by a laparoscopic and 26% by an open approach. 10 out of 103 patients did not undergo a colonic resection but instead an emergency colostomy/ ileostomy or oversewing of a bowel leak, in 8 cases performed laparoscopically. 44 patients have been operated for a benign disease (36 laparoscopic and 8 open procedures) and 59 patients have been treated for a malignant disease (40 laparoscopic and 19 open procedures). The average operating time for the laparoscopic resection was 160 minutes in comparison to 182 minutes for the open resection. The conversion rate (inclusive of non-resection procedures) was 5% for a benign disease and 11% for colorectal cancer. The minor complication rate was 16% in laparoscopic surgery and 30% in open surgery. We saw two major complications in both the open and laparoscopic groups (4%). Reoperation was necessary in one patient out of 103. The average postoperative hospital stay was 7.78 days for the laparoscopic and 16.6 days for the open group. The hospital mortality was 2.9%. CONCLUSION: The laparoscopic colorectal resection is a safe and beneficial procedure for the patient when used in experienced hands.

Colonic Neoplasms↗

PubMed2001

Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study.

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.

Adolescent↗

PubMed2001

The structure of the coliphage HK022 Nun protein-lambda-phage boxB RNA complex. Implications for the mechanism of transcription termination.

Nun protein from coliphage HK022 binds to phage boxB RNA and functions, in contrast to phage lambda N protein, as a transcriptional terminator. The basic Nun-(10-44) peptide contains the boxB RNA binding arginine rich motif, ARM. The peptide binds boxB RNA and competes with the phage lambda ARM peptide N-(1-36) as indicated by nuclear magnetic resonance (NMR) spectroscopy titrations. In two-dimensional nuclear Overhauser enhancement spectroscopy experiments boxB RNA in complex with Nun-(20-44) exhibits the same pattern of resonances as it does in complex with N peptides containing the ARM, and we could show that Nun-(20-44) forms a bent alpha-helix upon binding to the boxB RNA. The structure of the boxB RNA-bound Nun-(20-44) was determined on the basis of 191 intra- and 30 intermolecular distance restraints. Ser-24 is anchored to the lower RNA stem, and stacking of Tyr-39 and A7 is clearly experimentally indicated. Arg-28 shows numerous contacts to the RNA stem. Leu-22, Ile-30, Trp-33, Ile-37, and Leu-41 form a hydrophobic surface, which could be a recognition site for additional host factors such as NusG. Such a hydrophobic surface area is not present in N-(1-36) bound to boxB RNA.

Amino Acid Sequence↗

PubMed2001

Zinc inhibits the mixed lymphocyte culture.

The mixed lymphocyte culture (MLC) is an established clinical method for bone marrow transplantation, as it serves as an in vitro model for allogenic reaction and transplantation. We previously showed that cytokine release into the supernatant is a more specific and sensitive parameter for cross-reactivity in the MLC than the common measurement of cell proliferation. Therefore we tried to find an inhibitor of the MLC in vitro with the least side effects in vivo, measuring interferon (IFN)-gamma as one of the most important cytokines in posttransplant medicine. Earlier studies showed that zinc is an important trace element for immune function with both stimulatory and inhibitory effects on immune cells. We found that slightly elevated zinc concentrations (three to four times the physiological level), which do not decrease T-cell proliferation in vitro nor produce immunosuppressive effects in vivo, suppress alloreactivity in the mixed lymphocyte culture. In this report we analyzed the mechanism whereby zinc influences the MLC to possibly find a nontoxic way of immunosuppression.

Bone Marrow Transplantation↗

PubMed2000

Immobilization of BINOL by cross-linking copolymerization of styryl derivatives with styrene, and applications in enantioselective Ti and Al Lewis acid mediated additions of Et2Zn and Me3SiCN to aldehydes and of diphenyl nitrone to enol ethers

The chiral ligand 1,1'-bi-2-naphthol (BINOL) has been succesfully immobilized on polystyrene. Several dendritic and non-dendritic BINOL derivatives (3, and 13-17), bearing at least two polymerizable styryl groups, were prepared and fully characterized. Suspension copolymerization of the MOM- or TIPS-protected cross-linking BINOL ligands (MOM = methyloxymethyl, TIPS = triisopropylsilyl) with styrene, cleavage of the protecting-groups, and loading with a Lewis-acid afforded catalytically active polystyrene-supported BINOLates. The polymer-bound BINOLs p-3, and p-13-p-16 were tested in the Ti-BINOLate-mediated addition of Et2Zn to PhCHO. The enantioselectivities (up to 93%) and conversions obtained with the polymer-bound catalysts were in most cases identical (within experimental error) to those obtained with the unsubstituted 1,1'-bi-2-naphthol and with the non-polymerized BINOL cross-linkers under homogeneous conditions. Special focus was put on the reusability of the supported catalyst: the polymer-beads were used in up to 20 consecutive catalytic runs, with the best polymers showing no or only minor loss of selectivity. BINOL-polymers p-17, obtained by copolymerization of a 3,3'-distyryl-substituted BINOL 17a with styrene, were used in the BINOL. AlMe-mediated cycloaddition of diphenyl nitrone with alkyl vinyl ethers. In all cases the exo/endo selectivity (> or =92:8) and the enantioselectivities with which the exo-cycloadducts were formed (> or =95%) correspond to those observed in the homogeneous reactions. A dendritically cross-linked BINOL-polymer was also employed in the Ti-BINOLate-mediated cyanosilylation of pivalaldehyde. The enantiopurity of the cyanohydrine obtained in the first run was as high as in the homogeneous reaction (72%); surprisingly the catalytic performance of the supported catalyst increased steadily during the first catalytic cycles to reach 83%. Thus, cross-linking BINOLs can be succesfully incorporated into a polystyrene matrix (without racemization!) to give polymer-bound BINOL ligands that give excellent performance over many catalytic cycles with catalytic activities comparable with those of soluble analogues.

Journal Article↗

PubMed2000

Structural rearrangements of HIV-1 Tat-responsive RNA upon binding of neomycin B.

Binding of human immunodeficiency virus type 1 (HIV-1) transactivator (Tat) protein to Tat-responsive RNA (TAR) is essential for viral replication and is considered a promising starting point for the design of anti-HIV drugs. NMR spectroscopy indicated that the aminoglycosides neomycin B and ribostamycin bind to TAR and that neomycin is able to inhibit Tat binding to TAR. The solution structure of the neomycin-bound TAR has been determined by NMR spectroscopy. Chemical shift mapping and intermolecular nuclear Overhauser effects define the binding region of the aminoglycosides on TAR and give strong evidence for minor groove binding. Based on 15 nuclear Overhauser effect-derived intermolecular distance restraints, a model structure of the TAR-neomycin complex was calculated. Neomycin is bound in a binding pocket formed by the minor groove of the lower stem and the uridine-rich bulge of TAR, which adopts a conformation different from those known. The neamine core of the aminoglycoside (rings I and II) is covered with the bulge, explaining the inhibition of Tat by an allosteric mechanism. Neomycin reduces the volume of the major groove in which Tat is bound and thus impedes essential protein-RNA contacts.

ATPases Associated with Diverse Cellular Activitie↗

PubMed2000

Stimulation of endothelin B receptor modulates the inflammatory activation of rat astrocytes.

Inside the brain tissue, endothelins play numerous important biological roles. One of the targets, astrocytes, predominantly display endothelin receptor subtype B (ET(B)). On cultured primary rat astroglial cells, we analyzed the effect of IRL1620, a selective ET(B) receptor agonist, on the production of nitric oxide (NO) and the synthesis of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. We performed these experiments in the presence or absence of interferon-gamma (IFN-gamma) and/or lipopolysaccharide (LPS). IRL1620 decreases NO production under basal conditions and after IFN-gamma stimulation. However, during LPS-induced NO production, IRL1620 enhances this release. The basal IL-6 secretion and especially the LPS-induced synthesis are enhanced by the IRL1620 stimulation. The LPS-dependent TNF-alpha production is increased by the ET(B) stimulation. The IRL1620-induced decrease of basal NO production is not dependent on Ca2+ entry or on phospholipase C (PLC) activation, as shown by the use of LaCl3 and U73122, respectively. In the presence of LPS, the IRL1620 potentiation of NO production is inhibited by LaCl3 and U73122. The IRL1620-induced increase of IL-6 is dependent on PLC activation. These results suggest that endothelins can have dual effects depending on the costimulatory factors present. Endothelins thus have important immunomodulatory functions in the brain.

Animals↗

PubMed2000

Interleukin-4 enhances the in vitro precursor cell recruitment for tumor-specific T lymphocytes in patients with glioblastoma.

Previously the authors showed that interleukin-4 (IL-4), used in combination with IL-2, increases the reduced proliferation rate of T cells of glioblastoma-bearing patients after in vitro autologous immunization. In this report, they sought to determine whether this effect is caused by a direct mitogenic effect of IL-4, or rather by an indirect effect through an increased expression of the IL-2 receptor subunits or an enhanced recruitment of responsive cells. Flow cytometric analysis confirmed that the IL-2 receptor subunits are less expressed on circulating T cells from patients with glioblastoma than on those from healthy donors. Because no significant modification of the expression of the p55 and p75 subunits of the IL-2 receptor is observed in cultures treated with both IL-2 and IL-4, the reported enhanced proliferation rate cannot be attributed to an increased level of IL-2 receptor expression. Limiting dilution assays, using autologous target cell immunization, show that treatment with both cytokines (IL-2 plus IL-4) significantly increases the number of recruitable precursor cells without affecting their proliferation rate. These results indicate that IL-4 facilitates an immune response against the autologous tumor cells in glioblastoma-bearing patients by increasing the recruitable precursor T-cell frequency.

Glioblastoma↗

PubMed1999

Regional heterogeneity of the astroglial immunoreactive phenotype: effect of lipopolysaccharide.

In order to find out whether the concept of regional heterogeneity in astrocytes also applies to the immunoreactive phenotype, we studied cultured primary rat astrocytes originating from five different brain regions (cortex, hippocampus, striatum, septum, and brainstem).We investigated this heterogeneity through the ability of lipopolysaccharide (LPS) to differentially induce several parameters that are known to characterize activated astroglia: major histocompatibility complex (MHC) class II and intercellular adhesion molecule (ICAM)-1 expression, nitric oxide (NO) production, synthesis of interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). Under basal conditions, some of these parameters are already heterogeneic. The presence of LPS enhances these differences: expression of MHC class II increases after a 48-hour incubation with LPS, with brainstem and hippocampus astrocytes reaching the highest levels; NO production is induced by an LPS incubation, with the brainstem showing low NO production levels; septum and striatum instead show higher cytokine (TNF-alpha, IL-6) productions. The baseline expression of ICAM-1 also shows major regional differences, with the brainstem displaying the highest ICAM-1 expression. Our results demonstrate that the immunoreactive abilities of astrocytes show regional heterogeneities. This specialization may be implicated in the pathophysiological pathways of several neurodegenerative disorders.

Animals↗