Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Autocrine Communication”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 559 records · Page 31Linked to original sources
PubMed2000

Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation.

BACKGROUND: Interstitial fibroblasts play a critical role in renal fibrogenesis, and autocrine proliferation of these cells may account for continuous matrix synthesis. Basic fibroblast growth factor (FGF-2) is mitogenic for most cells and exerts intracrine, autocrine, and paracrine effects on epithelial and mesenchymal cells. The aims of the present studies were to localize and quantitate the expression of FGF-2 in normal and pathologic human kidneys and to study the in vitro effects of FGF-2 on proliferation, differentiation, and matrix production of isolated cortical kidney fibroblasts. METHODS: FGF-2 protein expression was localized by immunofluoresence double labelings in normal and fibrotic human kidneys. Subsequently, interstitial FGF-2 labeling was determined semiquantitatively in 8 normal kidneys and 39 kidneys with variable degrees of interstitial fibrosis and was correlated with the morphometrically determined interstitial cortical volume. In addition, FGF-2 expression was quantitated by immunoblot analysis in three normal and six fibrotic kidneys. FGF-2 mRNA was localized by in situ hybridizations. Seven primary cortical fibroblast lines were established, and expression of FGF-2 and FGF receptor-1 (FGFR-1) were examined. The effects of FGF-2 on cell proliferation were determined by bromodeoxyuridine incorporation and cell counts, those on differentiation into myofibroblasts by staining for alpha-smooth muscle actin, and those on matrix synthesis by enzyme-linked immunosorbent assay for collagen type I and fibronectin. Finally, proliferative activity in vivo was evaluated by expression of MIB-1 (Ki-67 antigen). RESULTS: In normal kidneys, FGF-2 expression was confined to glomerular, vascular, and a few tubular as well as interstitial fibroblast-like cells. The expression of FGF-2 protein was increased in human kidneys, with tubulointerstitial scarring correlating with the degree of interstitial fibrosis (r = 0.84, P < 0.01). Immunoblot analyses confirmed a significant increase in FGF-2 protein expression in kidneys with interstitial scarring. In situ hybridization studies demonstrated low-level detection of FGF-2 mRNA in normal kidneys. However, FGF-2 mRNA expression was robustly up-regulated in interstitial and tubular cells in end-stage kidneys, indicating that these cells are the source of excess FGF-2 protein. Primary cortical fibroblasts express FGF-2 and FGFR-1 in vitro. FGF-2 induced a robust growth response in these cells that could be blocked specifically by a neutralizing FGF-2 antibody. Interestingly, the addition of the neutralizing antibody alone did reduce basal proliferation up to 31.5%. In addition, FGF-2 induced expression of alpha-smooth muscle actin up to 1.6-fold, but no significant effect was observed on the synthesis of collagen type I and fibronectin. Finally, staining for MIB-1 revealed a good correlation of interstitial FGF-2 positivity with interstitial and tubular proliferative activity (r = 0.71, P < 0.01 for interstitial proliferation, N = 30). CONCLUSIONS: Interstitial FGF-2 protein and mRNA expression correlate with interstitial scarring. FGF-2 is a strong mitogen for cortical kidney fibroblasts and may promote autocrine fibroblast growth. Expression of FGF-2 correlates with interstitial and tubular proliferation in vivo.

Adult↗
PubMed2001

Renal fibroblast-like cells in Goodpasture syndrome rats.

BACKGROUND: The extent of renal fibrosis is the best predictor for functional outcomes in a variety of progressive renal diseases. Interstitial fibroblast-like cells (FbLCs) are presumably involved in the fibrotic process. However, such FbLCs have never been well characterized in the kidney. METHODS: We characterized renal FbLCs in the nephritic kidney (in which the number of FbLCs and extracellular matrix accumulation were significantly increased) with regards to their expression of phenotypic and functional markers using day 49 Goodpasture syndrome (GPS) rats. RESULTS: Within the renal cortical interstitium, there were a number of alpha-smooth muscle actin(+) (alpha-SMA(+)) FbLCs, negative for vimentin (VIM) and transforming growth factor-beta 1, and not equipped with well-developed rough endoplasmic reticulum and actin-stress fibers. All of these findings were incompatible with the typical features of granulation tissue alpha-SMA(+) myofibroblasts. On the other hand, FbLCs negative for alpha-SMA and VIM produced alpha1(I) procollagen in the nephritic kidney. CONCLUSION: A number of FbLC populations reside within the cortical interstitium of the kidney in GPS rats, each of which is likely to have developed independently in response to the local conditions of the nephritic kidney, contributing to renal fibrogenesis. Further studies are needed to clarify the key type of FbLC that orchestrates other members to produce renal fibrosis.

Actins↗
PubMed2002

Activin A: an autocrine regulator of cell growth and differentiation in renal proximal tubular cells.

BACKGROUND: Activin A is involved in tubular regeneration after ischemia/reperfusion injury. The present study was conducted to examine the role of activin A in cell growth, apoptosis and differentiation of tubular cells. METHODS: We performed cell proliferation assays (MTT assay, [3H]-thymidine incorporation) and apoptosis detection assays (nuclear staining, DNA ladder formation, TUNEL staining) using LLC-PK1 cells. Expression of activin and activin receptor in LLC-PK1 cells also were examined by real-time polymerase chain reaction (PCR) and immunostaining. Stable cell lines expressing the truncated type II activin receptor were generated and the phenotype of these cells was analyzed. RESULTS: Activin A inhibited DNA synthesis and cell growth in a dose-dependent manner and induced apoptosis in LLC-PK1 cells. The expression level of mRNA for the activin betaA subunit was markedly increased when the growth was stimulated. The expression of the type II activin receptor was observed in LLC-PK1 cells. The growth rate of cells expressing dominantly negative activin receptor was significantly faster than that of non-transfected cells. The expression level and pattern of cytokeratin and vimentin in these cells were quite different compared to non-transfected cells. When cultured in collagen gel, these cells formed multiple processes, which was not observed in non-transfected cells. Finally, the expression of Pax-2 was markedly elevated in these cells. CONCLUSIONS: Activin A acts as an autocrine inhibitor of cell growth, an inducer of apoptosis, and an important modulator of differentiation in cultured proximal tubular cells.

Activin Receptors, Type II↗
PubMed2003

Expression of NOS1 and soluble guanylyl cyclase by human kidney epithelial cells: morphological evidence for an autocrine/paracrine action of nitric oxide.

BACKGROUND: Nitric oxide plays an important role in the kidney through effects on both renal hemodynamics and tubular functions. Tubular epithelial cells are thus a target for nitric oxide. However, as to whether tubular epithelial cells endogeneously produce nitric oxide under physiologic conditions in human kidney is currently unknown. The aim of the present study was to characterize and localize in situ the nitric oxide synthase (NOS) isoforms (NOS1, NOS2, and NOS3) expressed in human normal kidney, and soluble guanylyl cyclase, the well-known target for nitric oxide. METHODS: Five complementary experimental approaches were used: (1) detection of NOS reductase activity by nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry, (2) immunolocalization of the NOS isoforms (NOS1, NOS2, NOS3), (3) immunoblot analysis, (4) quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis of NOS mRNA, and (5) measurement of NOS activity as the conversion rate of l-[14C]-arginine to l-[14C]-citrulline. In addition, in situ detection of soluble guanylyl cyclase was assessed by immunohistochemistry. RESULTS: All these techniques led to consistent results showing that epithelial cells of most tubules along the human nephron exhibit functional NOS1, with a corticomedullary gradient observed both at the protein and mRNA levels. Moreover, epithelial cells expressing NOS1 also express soluble guanylyl cyclase, indicating that these cells possess the machinery for autocrine/paracrine effect of nitric oxide. CONCLUSION: The present study demonstrates that NOS1 is strongly expressed in most tubules of the human nephron and therefore invites to consider epithelial cells as one of the major source of nitric oxide in the human kidney under physiologic conditions.

Autocrine Communication↗
PubMedDate not supplied

Control of oocyte growth and maturation by follicular cells and molecules present in follicular fluid. A review.

The aim of this review is to summarize the interactions between the oocyte and its surrounding granulosa cells which are involved in the control of oocyte growth or apoptosis as well as those playing a key role in the ability of the oocyte to undergo nuclear (resumption as meiosis to reach the MII stage) or cytoplasmic maturation (ability to fertilize and develop to the blastocyst stage). The respective roles of the oocyte and of the granulosa cells in controlling the initiation of growth are poorly understood. During the preantral follicular stage when most oocyte growth is achieved, a local regulation appears to be in operation involving growth factors such as fibroblast growth factor (FGF) or epidermal growth factor/transforming growth factor alpha (EGF/TGF alpha), together with two proteins (c-kit present on the oocyte's membrane and its ligand KL produced by granulosa cells). In-situ techniques used to detect apoptosis demonstrate apoptotic oocytes in the reserves of primordial follicles but seldom within preantral follicles (because it is too fast?). Proteins involved in cell death (bax) or cell survival (bcl2) are present in oocytes as well as compounds (TNF alpha, Fas) involved in the initiation of apoptosis. However, the molecular and cellular mechanisms triggering oocyte apoptosis are not fully clarified. Three approaches have been used to identify compounds which are relevant to the oocyte's nuclear or cytoplasmic maturation. a) Correlation between amounts of specific compounds in follicular fluid or within follicle cells and the oocyte's ability to mature. b) Analysis of the consequences of pharmacological disruption of mechanisms such as steroidogenesis on oocyte maturation. c) Analysis of the consequences of addition of graded amounts of specific compounds on oocyte maturation in defined media. Factors playing a key role in stimulating nuclear maturation appear to be epidermal growth factor (EGF) and the inhibin (cattle)/activin (rodents) family, while testosterone has an inhibitory effect. Cytoplasmic maturation of the oocyte appears to be stimulated by oestradiol, EGF and inhibin.

Animals↗
PubMed2003

Perturbation of autocrine/paracrine loops of burst-forming units of erythroid-derived cells in rHuEPO-hyporesponsive hemodialysis patients.

BACKGROUND: Quantitative or qualitative abnormalities of erythroid progenitors in patients with chronic renal failure (CRF) could be the major factor for recombinant human erythropoietin (rHuEPO) hyporesponsiveness and severe anemia in hemodialysis (HD) patients receiving rHuEPO therapy. METHODS: Purified 1 x 10(4) circulating CD34+ cells isolated from rHuEPO-hyporesponsive HD patients (EPO-H; n = 10), rHuEPO-responsive non-HD patients with CRF (EPO-R; n = 8), nonanemic HD patients without rHuEPO therapy (EPO-W/O; n = 10), and healthy volunteer controls (CON; n = 10) were subjected to a methylcellulose culture system supplemented with rHuEPO, recombinant human interleukin-3 (IL-3), recombinant human stem cell factor (SCF), and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) for 14 days. RESULTS: The average number of burst-forming units of erythroids (BFU-Es) was significantly less in the EPO-H group compared with the CON and EPO-W/O groups. Furthermore, colony size also was significantly smaller in the EPO-H group. Total RNAs were extracted from approximately 100 colonies/patient and subjected to complementary DNA expression array studies of 268 growth factors, cytokines, chemokines, and their receptors. A characteristic cluster upregulated in the EPO-R and EPO-W/O groups and downregulated in the EPO-H group was identified that contained various cytokines and growth factors, including IL-6, GM-CSF, vascular endothelial growth factor B, IL-9, IL-3, leukemia inhibitory factor, and interferon alpha-2, and such receptors as thrombopoietin receptor, IL-9 receptor, and colony-stimulating factor 1 receptor. CONCLUSION: These data suggest that the cross-talk network or autocrine/paracrine regulatory loop is critically impaired in BFU-E-derived cells in EPO-H patients, and investigation of these cluster genes would facilitate the development of novel therapeutic strategies for such patients.

Aged↗
PubMed2000

De novo expression of vascular endothelial growth factor in human pancreatic cancer: evidence for an autocrine mitogenic loop.

BACKGROUND & AIMS: The role of vascular endothelial growth factor (VEGF) and its receptors in tumor angiogenesis has been well established. We analyzed the expression pattern and biologic significance of VEGF and its receptors in human pancreatic cancer. METHODS: VEGF, KDR/flk-1, and flt-1 expression were examined by immunohistochemistry, in situ hybridization, reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and receptor phosphorylation. VEGF-stimulated mitogenesis was investigated by mitogen-activated protein kinase (MAPK) phosphorylation, transactivation of a c-fos promoter reporter construct, DNA synthesis assays, and stable transfection of a dominant-negative flk-1 complementary DNA (cDNA) construct. RESULTS: Compared with normal pancreas and chronic pancreatitis, VEGF and its receptors were overexpressed in pancreatic cancer. KDR and flt-1 were detected not only in endothelial cells but also in tumor cells. VEGF expression was observed in all human pancreatic tumor cell lines examined, and the KDR/flk-1 and flt-1 receptor was detected in 2 cell lines. VEGF treatment results in phosphorylation of MAPKs, transactivation of a c-fos promoter construct, and growth stimulation in KDR/flk-1-expressing cell lines, which could be blocked by VEGF antagonists. Furthermore, stable transfection of a dominant-negative flk-1 cDNA significantly inhibited tumor cell growth. CONCLUSIONS: These results not only support the important role of the VEGF/VEGF receptor system in pancreatic tumor biology but also suggest the existence of an autocrine/paracrine mitogenic loop for pancreatic cancer cells.

Adenocarcinoma↗
PubMed2002

Fractalkine-mediated signals regulate cell-survival and immune-modulatory responses in intestinal epithelial cells.

BACKGROUND & AIMS: In this study, we determined the signal transduction and functional consequences after ligand-specific activation of the fractalkine receptor CX3CR1 in human intestinal epithelial cells. METHODS: CX3CR1 expression in human colonic tissues and intestinal epithelial cell lines was determined by immunohistochemistry, immunoblotting, and reverse-transcription polymerase chain reaction. The regulation of mitogen-activated protein kinase (MAPK) activation was assessed by immunoblotting. Regulation of chemokine messenger RNA (mRNA) expression was determined by Northern blotting. NF-kappa B and p53 activation was assessed by electromobility shift assays. RESULTS: Fractalkine mediated the MEK-1 and G alpha i-dependent but phosphatidylinositol-3-kinase-independent activation of extracellular signal-regulated kinase-MAPK. Fractalkine activated NF-kappa B and p53 resulting in interleukin 8 and fractalkine mRNA expression. CX3CR1-mediated activation of intestinal epithelial cells was able to induce migration of human neutrophils into but not through the intestinal epithelial cell monolayer. CONCLUSIONS: CX3CR1 mediates distinct functional responses in intestinal epithelial cells, which include the autocrine regulation of cell-survival signals and activation of immune modulators, indicating a role of CX3CR1 in host defense mechanisms originating from the intestinal epithelium.

Adjuvants, Immunologic↗
PubMed2005

Autocrine/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin.

BACKGROUND & AIMS: The biliary tree is the target of cholangiopathies that are chronic cholestatic liver diseases characterized by loss of proliferative response and enhanced apoptosis of cholangiocytes, the epithelial cells lining the biliary tree. The endogenous factors that regulate cholangiocyte proliferation are poorly understood. Therefore, we studied the role of the neuroendocrine hormone serotonin as a modulator of cholangiocyte proliferation. METHODS: The presence of the serotonin 1A and 1B receptors on cholangiocytes was evaluated. We then tested whether the activation of such receptors by the administration of the selective agonists modifies cholangiocyte proliferation and functional activity both in vivo and in vitro. In addition, the intracellular signal mediating the serotonin receptor action in cholangiocytes was characterized. We studied the expression and secretion of serotonin by cholangiocytes and the effects of the neutralization of the secreted hormone on the growth of the biliary tree. RESULTS: Cholangiocytes express the serotonin 1A and 1B receptors. Their activation markedly inhibits the growth and choleretic activity of the biliary tree in the bile duct-ligated rat, a model of chronic cholestasis. Such changes are mediated by enhanced d -myo-inositol 1,4,5-triphosphate/Ca 2+ /protein kinase C signaling and the consequent inhibition of the adenosine 3',5'-cyclic monophosphate/protein kinase A/Src/extracellular signal-regulated kinase 1/2 cascade. Cholangiocytes secrete serotonin, the blockage of which enhances cholangiocyte proliferation in the course of cholestasis. CONCLUSIONS: We observed the existence of an autocrine loop based on serotonin that limits the growth of the biliary tree in the course of chronic cholestasis. Our novel findings might open new approaches for the management of cholangiopathies.

Animals↗
PubMed2005

Expression and role of Gas6 protein and of its receptor Axl in hepatic regeneration from oval cells in the rat.

BACKGROUND & AIMS: The growth arrest-specific gene 6 (Gas6) protein is a vitamin K-dependent protein that binds to the Axl subfamily of tyrosine kinase receptors and exerts antiapoptotic and proliferative effects. Because Gas6 plays a role in development and tissue remodelling, we studied its expression as well as that of its high-affinity receptor Axl in a well-characterized model of hepatic regeneration from precursor oval cells. METHODS: Hepatic regeneration was induced by treating rats with acetylaminofluorene followed by partial hepatectomy. RESULTS: Oval cell accumulation, which predominated in periportal regions, reached a maximum at days 9 and 14 after hepatectomy and declined thereafter. Oval cells expressed Gas6 protein and messenger RNA (mRNA). Axl mRNA hepatic levels paralleled the number of oval cells, and immunohistochemistry showed Axl expression in these cells. WB-F344 cells, a hepatocytic precursor cell line, also expressed Gas6 and Axl. Addition of Gas6 significantly increased the number of WB-F344 cells cultured with or without serum. Gas6 did not increase cell entry in the S phase of the cell cycle but inhibited 15-d-prostaglandin J2-induced WB-F344 cell apoptosis. CONCLUSIONS: Our data demonstrate an expression of Gas6 and of its receptor Axl by oval cells during hepatic regeneration. Because the Gas6/Axl couple protects from apoptosis a hepatocytic precursor cell line, these results strongly suggest that the Gas6/Axl couple favors oval cell accumulation in regenerating liver by an autocrine/paracrine mechanism.

Animals↗
PubMed2006

Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism.

BACKGROUND & AIMS: Vascular endothelial growth factor (VEGF) is secreted by several epithelia and modulates cellular functions by autocrine and paracrine mechanisms. The role of VEGF in cholangiocyte pathophysiology is unknown. We evaluated the role of VEGF in the regulation of cholangiocyte proliferation in rats that underwent bile duct ligation. METHODS: The expression of VEGF-A and VEGF-C and their receptors in cholangiocytes from normal and BDL rats was evaluated. Normal or BDL rats were treated with recombinant-VEGF-A or recombinant-VEGF-C or anti-VEGF antibodies, and proliferation of cholangiocytes was evaluated in situ by morphometry and in vitro by proliferating cell nuclear antigen immunoblots and MTS assay. In vitro, normal rat cholangiocyte cultures were stimulated with r-VEGF-A or r-VEGF-C and proliferation and signal transduction were evaluated. RESULTS: We found that (1) cholangiocytes express messenger RNA and protein for VEGF-A, VEGF-C, VEGF receptor 2 (VEGFR-2), and VEGF receptor 3 (VEGFR-3) and secrete VEGF; (2) secretion of VEGF and expression of VEGFR-2 and VEGFR-3 increases in BDL cholangiocytes; (3) blocking VEGF in vivo by anti-VEGF-A or anti-VEGF-C antibodies decreases cholangiocyte proliferation; (4) the in vivo administration of r-VEGF-A or r-VEGF-C induces cholangiocyte proliferation in normal rats; and (5) in vitro, VEGF-A increases normal rat cholangiocyte culture proliferation by activation of inositol 1,4,5-triphosphate/Ca2+/protein kinase C alpha and phosphorylation of Src/ERK1/2. CONCLUSIONS: Cholangiocytes secrete VEGF and express VEGFR-2 and VEGFR-3, all of which are amplified in BDL cholangiocytes. VEGF induces cholangiocyte proliferation by activation of inositol 1,4,5-triphosphate/[Ca2+]i/protein kinase C alpha and phosphorylation of Src/ERK1/2. VEGF mediates the adaptive proliferative response of cholangiocytes to cholestasis.

Animals↗
PubMed2006

Neonatal lung and airway injury: a role for neurotrophins.

Maintenance of patency in distal airways is essential for gas exchange in neonatal life, and its disruption may have long-lasting effects on respiratory function. However, neural mechanisms that regulate caliber of intrapulmonary airways during early postnatal life, and their disruption by hyperoxic exposure, have not been well characterized. We have previously shown that cholinergically mediated airway contractile responses in rat pups are upregulated after hyperoxic exposure, and that increased expression of neuropeptides, such as substance P, may be contributory. More recently, we have documented impairment of neurally mediated airway relaxation in response to hyperoxic stress associated with loss of nitric oxide and prostaglandin-induced airway relaxation as well as inhibition of long chain myosin phosphatase. Our most recent data demonstrate significantly enhanced expression of the neurotrophin, brain-derived neurotrophic factor (BDNF) and its high affinity specific tyrosine kinase B (TrkB) receptor in hyperoxia-exposed airway smooth muscle. The existence of a BDNF-TrkB receptor autocrine and paracrine loops in the airways provides a basis for understanding local regulatory mechanisms of airway homeostasis. A mechanistic role for BDNF-TrkB signaling in hyperoxia-induced airway hyperreactivity in early postnatal life could serve to modulate both afferent and efferent neural pathways that result in enhanced contractile responses of immature airways exposed to hyperoxic stress. Greater insight into these neural pathways may lead to future preventive strategies for preterm infants surviving neonatal intensive care and developing chronic lung disease.

Animals↗
PubMed2001

Wound-induced migration of rat hepatic stellate cells is modulated by endothelin-1 through rho-kinase-mediated alterations in the acto-myosin cytoskeleton.

Although migration of stellate cells during hepatic injury is essential for wound-healing and fibrosis of the liver, the extracellular and intracellular signals that regulate stellate cell migration are incompletely understood. In this study we tested the hypothesis that wound-induced migration of stellate cells is modulated by endothelin-1 (ET-1) through rho-kinase-mediated alterations in the acto-myosin cytoskeleton. To address this hypothesis, a method was established for direct visualization of wound-induced migration of culture-activated stellate cells with subcellular resolution. Migration in response to wounding was characterized by (1) plasma membrane ruffling and protrusion into the wound, (2) lamellipodia formation at the leading edge, (3) focal adhesion and stress fiber assembly, and (4) myosin reorganization. Exogenous ET-1 accelerated wound-induced migration of stellate cells, but did not alter wound-induced proliferation. Experiments using ET-1 antagonists in the absence of exogenous ET-1 showed that wound-induced migration was also stimulated by endogenous ET-1. Selective inhibition of rho-associated kinase decelerated migration in response to wounding. Moreover, inhibition of rho-associated kinase was distinguished by abrogation of focal adhesion formation, stress fiber assembly, and myosin reorganization. This study shows that rho-kinase-dependent alterations in the acto-myosin cytoskeleton contribute to wound-induced stellate cell migration, which is accelerated by both exogenous and endogenous ET-1. Consequently, these results provide important new evidence suggesting that, migration of stellate cells is modulated by paracrine and autocrine ET-1 stimulation via the action of rho-kinase on the acto-myosin cytoskeleton.

Actomyosin↗
PubMed2002

Autocrine/paracrine regulation of apoptosis in epithelial cells by prostaglandin E2.

This study was designed to investigate the effect of IL-1alpha-induced up-regulation of cyclooxygenase-2 (COX-2) on prostaglandin E(2) (PGE(2)) secretion and the subsequent phenotypic effects of PGE(2) on epithelial cells. The effect of IL-1alpha on COX-2 expression was investigated in the T24 bladder epithelial cell line following treatment with 0, 0.05, 0.5, 1 or 10 ng/ml IL-1alpha for 1, 2, 4 or 6 h. Quantitative PCR confirmed up-regulation of expression of COX-2 with maximal expression observed following treatment with 0.5 ng/ml IL-1alpha for 1 h. Co-treatment of the cells with 0.5 ng/ml IL-1alpha in the presence or absence of 100 ng/ml IL-1 receptor antagonist (RA) abolished the up-regulation in COX-2 expression confirming that the effect of IL-1alpha is mediated via its membrane-bound receptors. Treatment with 0.5 ng/ml IL-1alpha resulted in a time-dependent increase in PGE(2) secretion with maximal secretion detected at 24 and 48 h after stimulation with IL-1alpha. Co-treatment of the cells with IL-1alpha and IL-1RA or the COX-2 enzyme inhibitor NS398 abolished the IL-1alpha mediated secretion of PGE(2). Treatment of T24 cells with 100 nM PGE(2) resulted in a significant elevation in cAMP generation confirming the expression of functional PGE(2) receptors. Finally, the effect of exogenous treatment with PGE(2) on apoptosis of T24 cells was assessed using cell death detection ELISA. T24 cells were treated with camptothecin to induce apoptosis in the presence or absence of 50 or 100 nM PGE(2) or 10 microM forskolin. Treatment of T24 cells with increasing doses of camptothecin alone resulted in a significant increase in the induction of apoptosis (P<0.01). However, co-treatment of the cells with 50 or 100 nM PGE(2) or 10 microM forskolin resulted in the inhibition of induction of the apoptotic pathway by camptothecin. These data demonstrate that PGE(2) inhibits apoptosis of epithelial cells possibly via cAMP-dependent pathway.

Apoptosis↗
PubMed2000

Antithrombotic regulation in human endothelial cells by fibrinolytic factors.

Vascular endothelial cells (ECs) modulate the blood fibrinolytic system by secreting tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), and their inhibitor, type-1 plasminogen activator inhibitor (PAI-1). ECs also express t-PA receptors (t-PAR) and u-PA receptors (u-PAR) on their cell surfaces, assembling both enzymes to regulate the cellular fibrinolytic activity. In addition, ECs modulate these factors in response to several stimuli. Fibrin clots on ECs induce the up- and downregulation of t-PA and PAI-1 production, respectively, thus causing an effective lysis of the fibrin clot. Heat shock (43 degrees C) increases the expression of u-PA, t-PA, PAI-1, and u-PAR by which ECs become more fibrinolytic around the cells. Furthermore, because ECs possess t-PAR and u-PAR on their cell surfaces, the binding of t-PA and u-PA is a critical event, which affords ECs the localized and condensed fibrinolytic potential. Therefore, ECs play a central role in antithrombotic activity by regulating the levels of these fibrinolytic factors.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2002

Adenosine triphosphate release and purinergic regulation of cholangiocyte transport.

The discovery of purinergic receptors on almost every cell type studied to date suggests that purinergic signaling is a fundamental process regulating cell and organ level functions. Purinergic receptors have been found on all principal liver cell types, including liver parenchymal cells, or hepatocytes, and biliary epithelial cells, or cholangiocytes. Both hepatocytes and cholangiocytes are capable of the regulated release of adenosine triphosphate (ATP), and both cell types express a range of purinergic receptors to mediate cellular processes. The role of extracellular nucleotides in liver function is presently being elucidated. Extracellular ATP, in addition to autocrine regulation of liver cell volume, has recently been shown to play an important role in paracrine signaling to coordinate specific hepatocyte and cholangiocyte cellular responses. The findings that (1) cholangiocytes are capable of the regulated release of ATP into bile, (2) ATP is present in bile in concentrations capable of stimulating purinergic receptors, and (3) P2 receptor stimulation results in brisk Cl(-) channel activation and fluid secretion suggest an important role of extracellular ATP in the regulation of bile formation. This article highlights important developments in our understanding of the role of purinergic signaling in cholangiocyte transport and bile formation.

ATP-Binding Cassette Transporters↗
PubMed2002

Adrenocortical peptides: autocrine or paracrine regulators for the steroid hormone secretion or the cell proliferation?

There is accumulating evidence that indicates the production and secretion of some peptides by adrenal cortex and adrenocortical tumors. These peptides include adrenomedullin, proadrenomedullin N-terminal 20 peptide (PAMP), endothelin-1, cerebellin, urotensin-II etc., and appear to be involved in the regulation of steroid hormone secretion and the proliferation of adrenocortical cells as autocrine and/or paracrine factors. It is noteworthy that expression of adrenomedullin is induced by hypoxia and inflammatory cytokines in various cells, raising the possibility that the adrenocortical production of adrenomedullin (and probably PAMP) may be increased in some inflammatory and/or ischemic conditions, and these two peptides may modulate the states of inflammatory and/or ischemic disorders. In addition to adrenomedullin and PAMP, adrenal cortex and/or some adrenocortical tumors express endothelin-1, cerebellin, urotensin-II, etc. The adrenocortical peptides may form a novel autocrine or paracrine regulatory system for the steroid hormone secretion and the cell proliferation in the adrenal cortex, and involve in the pathophysiology of inflammatory, ischemic or neoplastic diseases of the adrenal cortex

Adrenal Cortex↗
PubMedDate not supplied

Differential autocrine regulation of intestine epithelial cell proliferation and differentiation by insulin-like growth factor (IGF) system components.

The mechanisms which regulate cell turnover in the intestinal epithelium are incompletely understood. The present study was performed to characterize the role of autocrine IGF system components in intestine epithelial cell proliferation and differentiation comparing rapidly growing crypt cells (IEC-6) with differentiating enterocytes (CaCo-2). The autocrine release of IGF-I, IGF-II and IGFBP-1 through -3 was determined by specific RIAs and western ligand blotting. In addition, binding and growth-promoting activity of insulin, IGF-I and IGF-II was investigated. Enterocytic differentiation was assessed by measuring the brush-border enzymes alkaline phosphatase and sucrase. During IEC-6 growth, the autocrine release of IGF-I and -II increased, whereas IGFBP-2 levels decreased. Specific receptors for IGF-I and IGF-II but not insulin could be detected. IGF-I was 100-fold more potent than insulin to stimulate IEC-6 cell proliferation. In contrast, CaCo-2 cells revealed higher binding of insulin than IGF-I/-II and no release of IGF-I. At switch from CaCo-2 cell proliferation to differentiation a marked increase in the secretion of IGF-II (10-fold), IGFBP-1 (2.5-fold), IGFBP-2 (3-fold), and IGFBP-3 (6-fold) was measured. Our data indicate that IGF system components differentially modulate enterocytic cell proliferation and differentiation.

Animals↗