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PubMed2001

Professor Toshio Ito: a clairvoyant in pericyte biology.

Ito cells are liver-specific pericytes which were first described as Fett Speicherung Zellen, the fat-storing cells encircling outside sinusoidal endothelial cells, in 1951 by the late professor Toshio Ito. His pioneering approaches for morphological characterization of the cells stimulate investigators to further examine their functional roles in liver homeostasis: a body of evidence has been accumulated in recent years showing that the cells play a crucial role in storage and delivery of vitamin A, regulation of sinusoidal tone and local blood supply, and tissue repair and fibrosis. It is now widely accepted that microvascular pericytes including Ito cells serve as a key player that controls angiogenesis. Furthermore, recent studies support a concept that Ito cells constitutes a bridging apparatus mediating bidirectional metabolic interactions between sinusoids and hepatocytes, utilizing prostanoids and/or gaseous mediators such as nitric oxide and carbon monoxide as signaling molecules. This article reviews researches on this liver-specific pericyte and its leading roles in recent development of pericyte biology.

Animals↗

PubMed2004

Bidirectional transepithelial IgG transport by a strongly polarized basolateral membrane Fcgamma-receptor.

The human MHC class I-related neonatal Fc receptor, hFcRn, mediates bidirectional transport of IgG across mucosal barriers. Here, we find that at steady state hFcRn distributes predominantly to an apical intracellular compartment and almost exclusively to the basolateral cell surface of polarized epithelial cells. It moves only transiently to the apical membrane. Ligand binding does not redistribute the steady state location of the receptor. Removal of the cytoplasmic tail that contains di-leucine and tryptophan-based endocytosis motifs or incubation at low temperature (18 degrees C) redistributes the receptor apically. The rates of endocytosis of the full-length hFcRn from the apical or basolateral membrane domains, however, are equal. Thus, the strong cell surface polarity displayed by hFcRn results from dominant basolateral sorting by motifs in the cytoplasmic tail that nonetheless allows for a cycle of bidirectional transcytosis.

Animals↗

PubMed1999

Functional analysis of rat renal organic anion transporter OAT-K1: bidirectional methotrexate transport in apical membrane.

Renal organic anion transporter OAT-K1 was stably transfected in MDCK cells and examined for its transport characteristics and membrane localization. OAT-K1 mediated both uptake and efflux of methotrexate in the apical membranes. Immunoblotting showed that the apparent molecular mass of the expressed OAT-K1 was 50 kDa, which was comparable to that found in the rat renal brush-border membranes. The OAT-K1-mediated methotrexate transport was significantly inhibited in the presence of several organic anions such as folate and sulfobromophthalein. These findings suggest that OAT-K1 mediates bidirectional methotrexate transport across the apical membranes, and may be involved in the renal handling of methotrexate.

Animals↗

PubMed1995

Tumor necrosis factor (TNF)-alpha directly inhibits human erythropoiesis in vitro: role of p55 and p75 TNF receptors.

Two tumor necrosis factor receptors (TNFRs) with molecular weights of 55 kD (TNFR-p55) and 75 kD (TNFR-p75) have recently been identified and cloned. In previous studies, TNFR-p55 has been shown to exclusively mediate bidirectional effects of TNF-alpha on committed bone marrow granulocyte-macrophage progenitor cells, whereas both TNFR-p55 and TNFR-p75 can mediate inhibition of primitive progenitors requiring multiple cytokines to proliferate. We show here that TNF-alpha potently and directly inhibits the in vitro growth of committed erythroid progenitor cells in response to multiple cytokine combinations, and that TNF-alpha-induced inhibition of burst-forming unit-erythroid colony formation is mainly mediated through TNFR-p55, although TNFR-p75-mediated inhibition could be observed on progenitors responsive to erythropoietin alone. Moreover, at low TNF-alpha concentrations (2 ng/mL), TNF-alpha stimulates interleukin-3-dependent in vitro growth of committed granulocyte-macrophage progenitor cells, whereas it potently inhibits erythroid progenitor cell proliferation, showing that one concentration of TNF-alpha can simultaneously and bidirectionally modulate interleukin-3-dependent growth of committed granulocyte-macrophage (stimulation) and erythroid progenitor cells (inhibition).

Antigens, CD↗

PubMed1995

Substance P (SP) mediates production of stem cell factor and interleukin-1 in bone marrow stroma: potential autoregulatory role for these cytokines in SP receptor expression and induction.

Substance P (SP) is a neuropeptide widely distributed in the nervous system. Its release within the bone marrow (BM) can mediate bidirectional neurohematopoietic communication via specific receptors: neurokinin-1R (NK-1R), NK-2R, or NK-3R. We have previously reported that SP effects on hematopoiesis are mediated by an NK-1-type receptor, the BM stroma, and growth factors. Here, we have studied the induction of stem cell factor (SCF) and interleukin-1 (IL-1) by SP in stroma. At 10(-9) mol/L SP, cytokine levels in supernatants were IL-1 alpha, 20 +/- 5 ng/mL; IL-1 beta, 40 +/- 10 ng/mL; and SCF, nondetectable; and the cell-associated levels were SCF, 21 +/- 2 ng/mL; IL-1 alpha, 90 +/- 6 ng/mL; and IL-1 beta, 45 +/- 3 ng/mL. Reverse transcriptase-polymerase chain reaction and ligand-binding studies with stroma stimulated by these two cytokines resulted in (1) NK-1-like receptor mRNA accumulation and (2) downregulation of SP binding sites (day 1) followed by an upregulation (day 3). Low numbers of high-affinity receptors were expressed by day 1 but not by day 3. The results indicate that SP induces IL-1 and SCF in stroma and that these cytokines have the potential to autoregulate NK-R.

Adipose Tissue↗

PubMed1995

Exchange of oxidized cholesteryl linoleate between LDL and HDL mediated by cholesteryl ester transfer protein.

This study examines the cholesteryl ester transfer protein (CETP)-mediated exchange of cholesteryl linoleate hydroperoxide (Ch18:2-OOH) and cholesteryl linoleate hydroxide (Ch18:2-OH) between low density lipoprotein (LDL) and high density lipoprotein (HDL). When [3H]Ch18:2-OOH- and [3H]18:2-OH-labeled LDL were incubated at 37 degrees C for 0-24 h with unoxidized HDL and purified CETP, Ch18:2-OOH and Ch18:2-OH accumulated in the HDL. Similarly, when incubations were carried out with [3H]Ch18:2-OOH- and [3H]Ch18:2-OH-labeled HDL, unoxidized LDL, and CETP, Ch18:2-OOH and Ch18:2-OH accumulated in the LDL. Comparable results were obtained for the CETP-mediated transfer of [3H]Ch18:2-OH alone from LDL to HDL. Transfer to HDL of oxidized cholesteryl linoleate from [3H]Ch18:2-OOH- and [3H]Ch18:2-OH-labeled LDL was comparable to that of unoxidized cholesteryl linoleate (Ch18:2). However, the rate of transfer of [3H]Ch18:2-OOH and [3H]Ch18:2-OH from LDL to HDL increased linearly as the molar ratio of acceptor (HDL) to donor (oxidized LDL) particles in the incubation increased from 0.5:1 to 10:1. This increased rate of exchange was accompanied by an increased proportion of the oxidized Ch18:2 being present as the hydroxide rather than hydroperoxide. Further increases in the molar ratio of HDL to oxidized LDL particles neither affected the transfer rate nor the extent of reduction of Ch18:2-OOH to Ch18:2-OH. We therefore conclude that i) CETP mediates bidirectional transfers of Ch18:2-OOH and Ch18:2-OH between HDL and LDL; ii) CETP does not distinguish between Ch18:2-OOH, Ch18:2-OH, and Ch18:2 as it mediates their exchange between HDL and LDL; and iii) association with HDL hastens the reduction of Ch18:2-OOH to Ch18:2-OH.

Adult↗

PubMed1991

Identification of a multimer resolution system involved in stabilization of the Salmonella dublin virulence plasmid pSDL2.

The Salmonella dublin virulence plasmid pSDL2 is a low-copy-number plasmid that is highly conserved in its host. Deletion of the 8-kb EcoRI C fragment downstream of the virulence region leads to plasmid instability and formation of multimers. We identified a multimer resolution system in the EcoRI C fragment composed of a trans-acting resolvase gene and a cis-acting resolution site. The resolvase gene, rsd, maps within a 2-kb EcoRV fragment and appears to be part of a multicistronic unit together with at least two other genes of unknown function. The derived protein, 28.7-kDa in size, is almost identical to the D protein of miniF. The C-terminal region was shown to have substantial similarity to the conserved C-terminal domains of the site-specific recombinases of the integrase family. The cis-acting resolution site, crs, is located upstream of rsd within a 628-bp SmaI-HpaI fragment. It contains eight direct incomplete 17-bp repeats followed by a segment rich in indirect repeats, the latter being homologous to the oriV1 sequence of miniF. crs contains the crossover site for specific recombination and mediates bidirectional promoter activity. A replicative function in analogy to that of oriV1 of F could not be demonstrated. The multimer resolution system was shown to stabilize pACYC184 and is dependent on the recA-mediated formation of multimeric plasmids. Screening different Salmonella serovars with a pSDL2-specific recombination assay revealed that only strains harboring a virulence plasmid encode for resolvase activity. Our results suggest that site-specific recombination contributes to the stable inheritance of pSDL2 and other Salmonella virulence plasmids.

Amino Acid Sequence↗

PubMed2005

Identification of neuroprotective properties of anti-MAG antibody: a novel approach for the treatment of stroke?

The inhibitory activity of myelin-associated glycoprotein (MAG) on neurons is thought to contribute to the lack of regenerative capacity of the CNS after injury. The interaction of MAG and its neuronal receptors mediates bidirectional signaling between neurons and oligodendrocytes. The novel finding that an anti-MAG monoclonal antibody not only possesses the ability to neutralise the inhibitory effect of MAG on neurons but also directly protects oligodendrocytes from glutamate-mediated oxidative stress-induced cell death is reported here. Furthermore, administration of anti-MAG antibody (centrally and systemically) starting 1 hour after middle cerebral artery occlusion in the rat significantly reduced lesion volume at 7 days. This neuroprotection was associated with a robust improvement in motor function compared with animals receiving control IgG1. Together, these data highlight the potential for the use of anti-MAG antibodies as therapeutic agents for the treatment of stroke.

Animals↗

PubMed2000

Epithelial-mesenchymal interactions in the pathogenesis of asthma.

During lung development, repair, and inflammation, local production of cytokines (eg, transforming growth factor-beta) and growth factors (eg, epidermal growth factor) by epithelial and mesenchymal cells mediate bidirectional growth control effectively creating an epithelial-mesenchymal trophic unit. In asthma the bronchial epithelium is highly abnormal, with structural changes involving separation of columnar cells from their basal attachments and functional changes including increased expression and release of proinflammatory cytokines, growth factors, and mediator-generating enzymes. Beneath this damaged structure there is an increase in the number of subepithelial myofibroblasts that deposit interstitial collagens causing thickening and increased density of the subepithelial basement membrane. Our recent studies suggest that the extent of epithelial damage in asthma may be the result of impaired epidermal growth factor receptor-mediated repair. In view of the close spatial relationship between the damaged epithelium and the underlying myofibroblasts, we propose that impaired epithelial repair cooperates with the T(H)2 environment to shift the set point for communication within the trophic unit. This leads to myofibroblast activation, excessive matrix deposition, and production of mediators that propagate and amplify the remodeling responses throughout the airway wall.

Asthma↗

PubMed1999

Evidence of glutathione transporter in rat brain synaptosomal membrane vesicles.

Glutathione (GSH) transport was studied in synaptosomal membrane vesicles (SMV) of rat cerebral cortex. The present study shows that GSH uptake into SMV occurs very quickly in a time-dependent manner into an osmotically active intravesicular space. The initial rate of transport followed Michealis-Menten saturation kinetics with a Km 4.5+/-0.8 microM that shows a high affinity of the transporter for GSH. Therefore GSH uptake in SMV occurs by a mediated transport system which can be activated by either an inward gradient of cations, like Na+ or K+, or membrane depolarization. These results, together with those obtained by valinomycin-induced K+ diffusion potential, indicate that GSH synaptosomal transport is electrogenic by a negative charge transfer. The increase of GSH uptake measured by trans-stimulation experiments confirms a GSH bidirectional mediated transport which seems susceptible of modulation by changes in ionic fluxes and in the membrane potential. These results may indicate a possible involvement of this transporter in the role suggested for GSH in synaptic neurotransmission; also considering that GSH precursor of neuroactive aminoacids (glycine, glutamate), may contribute to regulate their level in synapses. Finally, a GSH transporter in synaptosomes may contribute to maintaining the GSH homeostasis in cerebral cortex, where decreases of GSH levels have been related to susceptibility to neuropathologies.

Animals↗

PubMed2003

Acute regulation of the SLC26A3 congenital chloride diarrhoea anion exchanger (DRA) expressed in Xenopus oocytes.

Mutations in the human SLC26A3 gene, also known as down-regulated in adenoma (hDRA), cause autosomal recessive congenital chloride-losing diarrhoea (CLD). hDRA expressed in Xenopus oocytes mediated bidirectional Cl--Cl- and Cl--HCO3- exchange. In contrast, transport of oxalate was low, and transport of sulfate and of butyrate was undetectable. Two CLD missense disease mutants of hDRA were nonfunctional in oocytes. Truncation of up to 44 C-terminal amino acids from the putatively cytoplasmic C-terminal hydrophilic domain left transport function unimpaired, but deletion of the adjacent STAS (sulfate transporter anti-sigma factor antagonist) domain abolished function. hDRA-mediated Cl- transport was insensitive to changing extracellular pH, but was inhibited by intracellular acidification and activated by NH4+ at acidifying concentrations. These regulatory responses did not require the presence of either hDRA's N-terminal cytoplasmic tail or its 44 C-terminal amino acids, but they did require more proximate residues of the C-terminal cytoplasmic domain. Although only weakly sensitive to inhibition by stilbenes, hDRA was inhibited with two orders of magnitude greater potency by the anti-inflammatory drugs niflumate and tenidap. cAMP-insensitive Cl--HCO3- exchange mediated by hDRA gained modest cAMP sensitivity when co-expressed with cystic fibrosis transmembrane conductance regulator (CFTR). Despite the absence of hDRA transcripts in human cell lines derived from CFTR patients, DRA mRNA was present at wild-type levels in proximal colon and nearly so in the distal ileum of CFTR(-/-) mice. Thus, pharmacological modulation of DRA might be a useful adjunct treatment of cystic fibrosis.

Animals↗

PubMed2003

Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats.

The present study provides the first evidence that signaling occurs between B-ephrins and EphB receptors in the adult CNS in response to injury. Specifically, our combined histological and biochemical data indicate that two members of the B-class of ephrins and Eph receptors, ephrin-B2 and EphB2, are expressed by astrocytes and meningeal fibroblasts, respectively, in the adult spinal cord. In response to thoracic spinal cord transection lesions, ephrin-B2 and EphB2 protein levels exhibit an initial decrease (1 d after lesion), followed by a significant increase by day 14. Immunohistochemical data indicate that ephrin-B2 is expressed by reactive CNS astrocytes, and EphB2 is present on fibroblasts invading the lesion site from the adjacent meninges. During the first 3 d after injury, there is intermingling of ephrin-B2-expressing reactive astrocytes at the lesion surface with EphB2-containing fibroblasts that is concurrent with bidirectional activation (phosphorylation) of ephrin-B2 and EphB2. By 7 d, both cell types are establishing restricted cellular domains containing dense networks of cells and interweaving processes. This astroglial-meningeal fibroblast scar is fully developed by day 14 when there is strict segregation of ephrin-B2-expressing astrocytes from EphB2-positive meningeal fibroblasts. These morphological changes are concomitant with a simultaneous decrease in ephrin-B2 and EphB2 activation. These observations provide strong evidence that cell contact-mediated bidirectional signaling between ephrin-B2 on reactive astrocytes and EphB2 on meningeal fibroblasts is an early event in the cellular cascades that result in the development of the glial scar and the exclusion of meningeal fibroblasts from the injured spinal cord.

Animals↗

PubMed1992

Bidirectional control by glycyrrhizin of the growth response of lymphocytes stimulated through a receptor-bypassed pathway.

This study demonstrates a unique action of glycyrrhizin (GL) in bidirectionally controlling the growth response of lymphocytes stimulated through a receptor-bypassed pathway by calcium ionophore A23187 and phorbol 12-myristate 13-acetate (PMA). GL up-regulated the response of lymphocytes in vitro to lower concentrations of A23187 and PMA, and down-regulated the response to higher concentrations. We also provide evidence that GL controls the response of lymphocytes of different cell types or maturation stages in different ways, probably because these lymphocytes require different levels of signals as optimum. Finally, the GL-mediated bidirectional controls of the lymphocyte growth response were shown to be adherent cell-independent. The bidirectional controls demonstrated may be significant in normalizing the lymphocyte responses to very weak or very high stimuli.

Animals↗

PubMed1998

A 69-base pair fragment derived from human transcobalamin II promoter is sufficient for high bidirectional activity in the absence of a TATA box and an initiator element in transfected cells. Role of an E box in transcriptional activity.

A 69-base pair (bp) (-581/-513) fragment derived from human transcobalamin II distal promoter constructed upstream of a chloramphenicol acetyltransferase reporter gene demonstrated high bidirectional promoter activity in transfected epithelial Caco-2 cells. DNase I footprinting, gel mobility shift, supershift, and mutagenesis studies with the 69-bp fragment demonstrated that a GC box (-568/-559) and an E box (-523/-528), which interacted with Sp1/Sp3 and USF1/USF2 (where USF is upstream stimulatory factor), respectively, were required for the full transcriptional activity of this fragment. Whereas mutations in the GC box reduced the promoter activity by 50%, mutations in the E box alone or in both the E box and GC box resulted in 90% loss of transcriptional activity. The essential role of the E box in the bidirectional promoter activity was further demonstrated by transient transfection in Caco-2, K-562, and HeLa cells using a 29-bp (-541/-513) fragment that contained only the E box. Based on these results we suggest that 1) the E box is essential for both the GC box-dependent and -independent promoter activity of the 69-bp fragment, 2) cooperative interactions between Sp1/Sp3 and USFs are required for the full activation of the 69-bp promoter activity, and 3) the single E box is able to mediate bidirectional transcription in transfected cells in the absence of an obvious TATA box or a known initiator element.

Base Sequence↗

PubMed2006

Sprouty genes control diastema tooth development via bidirectional antagonism of epithelial-mesenchymal FGF signaling.

Unlike humans, who have a continuous row of teeth, mice have only molars and incisors separated by a toothless region called a diastema. Although tooth buds form in the embryonic diastema, they regress and do not develop into teeth. Here, we identify members of the Sprouty (Spry) family, which encode negative feedback regulators of fibroblast growth factor (FGF) and other receptor tyrosine kinase signaling, as genes that repress diastema tooth development. We show that different Sprouty genes are deployed in different tissue compartments--Spry2 in epithelium and Spry4 in mesenchyme--to prevent diastema tooth formation. We provide genetic evidence that they function to ensure that diastema tooth buds are refractory to signaling via FGF ligands that are present in the region and thus prevent these buds from engaging in the FGF-mediated bidirectional signaling between epithelium and mesenchyme that normally sustains tooth development.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Oxidation of LDL enhances the cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester transfer rate to HDL, bringing on a diminished net transfer of cholesteryl ester from HDL to oxidized LDL.

Cholesteryl ester transfer protein (CETP) plays a controversial role in atherogenesis by contributing to the net transfer of high density lipoprotein (HDL) cholesteryl ester (CE) to the liver via apolipoprotein-B-containing lipoproteins (apoB-LP). We evaluated in vitro the CETP-mediated bidirectional transfer of CE from HDL to the chemically modified pro-atherogenic low density lipoprotein (LDL) particles. Acetylated or oxidized (ox) LDL, either unlabeled or [3H]-CE labeled, were incubated with [14C]-CE-HDL in the presence of the lipoprotein-deficient plasma fraction (d>1.21 g/ml) as the source of CETP. The amount of radioactive CE transferred was determined after dextran sulfate/MgCl(2) precipitation of LDL. The results showed a 1.4-2.8-fold lower HDL-CE transfer to acetylated LDL while no effect was observed on the CE transfer to oxidized LDL. However, the reverse transfer rate of [3H]CE-LDL to HDL was 1.4-3.6 times greater when LDL was oxidized than when it was intact. Overall, HDL(2) was better than HDL(3) as donor of CE to native LDL, probably reflecting the relatively greater CE content of HDL(2). Oxidation of LDL enhanced the CETP-mediated cholesteryl ester transfer rate to HDL, bringing on a reduced net transfer rate of cholesteryl ester from HDL to ox LDL. This may diminish the oxLDL particle's atherogenic effect.

Carrier Proteins↗

PubMed2003

Bidirectional modulation of GABA release by presynaptic glutamate receptor 5 kainate receptors in the basolateral amygdala.

The activation of kainate receptors modulates GABAergic synaptic transmission, but the mechanisms are currently a matter of intense debate. In the basolateral amygdala (BLA), the glutamate receptor 5 (GluR5) subunit of kainate receptors is heavily expressed, and GluR5 antagonists block a novel form of synaptic plasticity; yet little is known about the role of GluR5-containing kainate receptors in the physiology of the amygdala. Here we show that GluR5 agonists bidirectionally modulate the strength of synaptic transmission from GABAergic interneurons to pyramidal cells in a concentration-dependent manner. Low concentrations of (RS)-S-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) (ATPA) (0.3 microm) or glutamate (5 microm) reduced the number of failures of GABAergic synaptic transmission and enhanced the frequency of miniature IPSCs (mIPSCs). High concentrations of ATPA (10 microm) or glutamate (200 microm) increased the number of synaptic failures and reduced the frequency of mIPSCs. The facilitation or suppression of GABAergic transmission by the GluR5 agonists did not require activation of voltage-gated calcium channels or presynaptic GABA(B) receptors. It was also found that extracellular, endogenous glutamate tonically reduces the rate of failures of GABAergic transmission. These results suggest that the terminals of GABAergic neurons in the BLA carry two subtypes of GluR5-containing kainate receptors, which have different agonist affinities and activate opposing mechanisms of action. The GluR5-mediated, bidirectional modulation of GABA release by glutamate in the BLA may play an important role in the regulation of synaptic plasticity and neuronal excitability in this structure, under normal and pathological conditions.

Amygdala↗

PubMed2003

An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain.

The water channel AQP4 is concentrated in perivascular and subpial membrane domains of brain astrocytes. These membranes form the interface between the neuropil and extracerebral liquid spaces. AQP4 is anchored at these membranes by its carboxyl terminus to alpha-syntrophin, an adapter protein associated with dystrophin. To test functions of the perivascular AQP4 pool, we studied mice homozygous for targeted disruption of the gene encoding alpha-syntrophin (alpha-Syn(-/-)). These animals show a marked loss of AQP4 from perivascular and subpial membranes but no decrease in other membrane domains, as judged by quantitative immunogold electron microscopy. In the basal state, perivascular and subpial astroglial end-feet were swollen in brains of alpha-Syn(-/-) mice compared to WT mice, suggesting reduced clearance of water generated by brain metabolism. When stressed by transient cerebral ischemia, brain edema was attenuated in alpha-Syn(-/-) mice, indicative of reduced water influx. Surprisingly, AQP4 was strongly reduced but alpha-syntrophin was retained in perivascular astroglial end-feet in WT mice examined 23 h after transient cerebral ischemia. Thus alpha-syntrophin-dependent anchoring of AQP4 is sensitive to ischemia, and loss of AQP4 from this site may retard the dissipation of postischemic brain edema. These studies identify a specific, syntrophin-dependent AQP4 pool that is expressed at distinct membrane domains and which mediates bidirectional transport of water across the brain-blood interface. The anchoring of AQP4 to alpha-syntrophin may be a target for treatment of brain edema, but therapeutic manipulations of AQP4 must consider the bidirectional water flux through this molecule.

Animals↗