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Results for “Autocrine Communication”

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At least 685 records · Page 38Linked to original sources
PubMed2003

Hypoxia induces an autocrine-paracrine survival pathway via platelet-derived growth factor (PDGF)-B/PDGF-beta receptor/phosphatidylinositol 3-kinase/Akt signaling in RN46A neuronal cells.

In neurons, hypoxia activates intracellular death-related pathways, yet the antiapoptotic mechanisms triggered by hypoxia remain unclear. In RN46A neuronal cells, minimum media growth conditions induced cell death as early as 12 h after the cells were placed in these conditions (i.e., after removal of B-27 supplement). However, apoptosis occurred in hypoxia (1% O2) only after 48 h, and in fact hypoxia reduced the apoptosis associated with trophic factor withdrawal. Furthermore, hypoxia induced time-dependent increases in expression of platelet-derived growth factor (PDGF) B mRNA and protein, as well as PDGF-beta receptor phosphorylation. Although exogenous PDGF-BB induced only transient Akt activation, hypoxia triggered persistent activation of Akt for up to 24 h. Inhibition of phosphatidylinositol 3-kinase (PI3K) or of PDGF-beta receptor phosphorylation abrogated both hypoxia-induced and exogenous PDGF-BB-induced Akt phosphorylation, and it completely abolished hypoxia-induced protection from media supplement deprivation, which suggests that the long-lasting activation of Akt during hypoxia and the prosurvival induction were due to endogenously generated PDGF-BB. Furthermore, these inhibitors decreased hypoxia-inducible factor 1alpha (HIF-1alpha) DNA binding, which suggests that the PDGF/PDGF-beta receptor/Akt pathway induces downstream HIF-1alpha gene transcription. We conclude that in RN46A neuronal cells, hypoxia activates an autocrine-paracrine antiapoptotic mechanism that involves up-regulation of PDGF-B and PDGF-beta receptor-dependent activation of the PI3K/Akt signaling pathway to induce downstream transcription of survival genes.

Apoptosis↗
PubMed2003

A novel laminin-induced LPA autocrine loop in the migration of ovarian cancer cells.

We have reported previously that levels of lysophosphatidic acid (LPA) are elevated in the blood and ascites from patients with ovarian cancer. LPA stimulates proliferation of ovarian cancer cells and has been proposed as an autocrine growth factor. Here, we show that a novel autocrine loop of LPA promotes the migration of ovarian cancer cells, which is a critical step of tumor metastasis. We report that laminin, but not other extracellular matrix proteins, induces LPA production in ovarian cancer cells. A neutralizing antibody against beta1 integrin and a calcium-independent phospholipase A2-specific inhibitor, HELSS, block both LPA production and the haptotactic activity of laminin. Exogenously added LPA restores the migratory ability of HEY ovarian cancer cells to laminin. These data suggest that laminin-induced cell migration is mediated by LPA. We further show that a specific receptor for LPA, LPA3, is required for mediating the chemotactic activity of LPA. In addition, we show that cytosolic PLA2 is required for cell migration and its activation is phosphatidylinositol-3 kinase-dependent. These findings have revealed a new mechanism of crosstalk between a beta1 integrin receptor and a G protein-coupled receptor.

Autocrine Communication↗
PubMed2003

Leptin is an autocrine/paracrine regulator of wound healing.

Leptin, a 16 kDa pleiotropic cytokine primarily expressed in adipose tissue, has been shown to cause multiple systemic biological actions. Recently, leptin has also been documented as an important component of the wound healing process and its receptor appears to be expressed in wound tissue. We have previously demonstrated that leptin is a potent angiogenic factor exerting direct effects on endothelial cells and that transcription of its encoding gene is regulated by hypoxia. Here, we hypothesize that leptin expression is acutely up-regulated in the ischemic tissue of experimental wounds. Using a combination of in situ hybridization and quantitative RT-PCR experiments, we show that leptin expression is rapidly and steadily up-regulated in skin tissue from incisional and excisional wounds. By immunohistochemistry, we demonstrate increased and sustained leptin protein levels in basal keratinocytes, blood vessel walls, and fibroblasts. To determine whether leptin is required for normal healing, excisional wounds were treated with neutralizing anti-leptin antibodies. This treatment markedly hampered healing progression and prevented wound closure and contraction. Finally, a transient rise in circulating blood leptin levels was detected within the first 24 h after inflicting the injury; we present evidence suggesting that this elevation is due to increased leptin production at the ischemic wound site. We conclude that leptin is acutely up-regulated in the injured skin and propose that this local production of leptin serves a critical functional role as an autocrine/paracrine regulator of normal wound healing.

Animals↗
PubMed2004

Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance.

It has been historically assumed that the pineal gland is the major source of melatonin (N-acetyl-5-methoxytryptamine) in vertebrates. Melatonin plays a central role in fine-tuning circadian rhythms in vertebrate physiology. In addition, melatonin shows a remarkable functional versatility exhibiting antioxidant, oncostatic, antiaging, and immunomodulatory properties. Melatonin has been identified in a wide range of organisms from bacteria to human beings. Its biosynthesis from tryptophan involves four well-defined intracellular steps catalyzed by tryptophan hydroxylase, aromatic amino acid decarboxylase, serotonin-N-acetyltransferase, and hydroxyindole-O-methyltransferase. Here, for the first time, we document that both resting and phytohemagglutinin-stimulated human lymphocytes synthesize and release large amounts of melatonin, with the melatonin concentration in the medium increasing up to five times the nocturnal physiological levels in human serum. Moreover, we show that the necessary machinery to synthesize melatonin is present in human lymphocytes. Furthermore, melatonin released to the culture medium is synthesized in the cells, because blocking the enzymes required for its biosynthesis or inhibiting protein synthesis in general produced a significant reduction in melatonin release. Moreover, this inhibition caused a decrease in IL-2 production, which was restored by adding exogenous melatonin. These findings indicate that in addition to pineal gland, human lymphoid cells are an important physiological source of melatonin and that this melatonin could be involved in the regulation of the human immune system, possibly by acting as an intracrine, autocrine, and/or paracrine substance.

Acetylserotonin O-Methyltransferase↗
PubMed2004

Heart infarct in NOD-SCID mice: therapeutic vasculogenesis by transplantation of human CD34+ cells and low dose CD34+KDR+ cells.

Hematopoietic (Hem) and endothelial (End) lineages derive from a common progenitor cell, the hemangioblast: specifically, the human cord blood (CB) CD34+KDR+ cell fraction comprises primitive Hem and End cells, as well as hemangioblasts. In humans, the potential therapeutic role of Hem and End progenitors in ischemic heart disease is subject to intense investigation. Particularly, the contribution of these cells to angiogenesis and cardiomyogenesis in myocardial ischemia is not well established. In our studies, we induced myocardial infarct (MI) in the immunocompromised NOD-SCID mouse model, and monitored the effects of myocardial transplantation of human CB CD34+ cells on cardiac function. Specifically, we compared the therapeutic effect of unseparated CD34+ cells vs. PBS and mononuclear cells (MNCs); moreover, we compared the action of the CD34+KDR+ cell subfraction vs. the CD34+KDR- subset. CD34+ cells significantly improve cardiac function after MI, as compared with PBS/MNCs. Similar beneficial actions were obtained using a 2-log lower number of CD34+KDR+ cells, while the same number of CD34+KDR- cells did not have any effects. The beneficial effect of CD34+KDR+ cells may mostly be ascribed to their notable resistance to apoptosis and to their angiogenic action, since cardiomyogenesis was limited. Altogether, our results indicate that, within the CD34+ cell population, the CD34+KDR+ fraction is responsible for the improvement in cardiac hemodynamics and hence represents the candidate active CD34+ cell subset.

Animals↗
PubMed2004

Does dysregulated expression of a deregulated viral GPCR trigger Kaposi's sarcomagenesis?

In 1994, the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) was identified as the etiologic agent of Kaposi's sarcoma (KS). KSHV has since been associated with two additional AIDS-related malignancies: primary effusion lymphomas (PEL) and multicentric Castleman's disease (MCD). Although molecular characterization of the KSHV genome has revealed several candidate oncogenes, infection with KSHV alone is not sufficient to cause KS, suggestive of an accomplice in KS initiation. Recent experimental evidence supports a key role for a particular KSHV gene, a constitutively-active G-protein-coupled receptor (vGPCR), in the development of KS. However, it is unclear how a lytic gene expressed in cells destined to die can cause cancer. Here we propose that dysregulation of the viral gene program may lead to nonlytic vGPCR expression. Several candidate cofactors (e.g., HIV-1 Tat, inflammation, aborted lytic cycle progression) are identified that may trigger vGPCR dysregulation, enabling oncogenic signaling pathways up-regulated by vGPCR, combined with the paracrine secretions from vGPCR-expressing cells, to promote the initiation of KS. If KS is indeed dependent on vGPCR dysregulation, then the development of new therapeutic modalities specifically targeting this viral protein or its downstream targets may ultimately prove to be the most effective treatment strategy for this enigmatic disease.

Animals↗
PubMed2004

Lycopene and vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model.

Epidemiological studies have consistently associated high intakes of lycopene or vitamin E with a reduced prostate cancer risk. Both compounds were tested in the MatLyLu Dunning prostate cancer model to gain insight into the in vivo action of lycopene and vitamin E. Supplementation for 4 weeks with 200 ppm lycopene, 540 ppm vitamin E, or both led to plasma levels comparable with those in humans. Both compounds also accumulated in tumor tissue. Macroscopic evaluation of the tumors by magnetic resonance imaging showed a significant increase in necrotic area in the vitamin E and the lycopene treatment groups. Microarray analysis of tumor tissues revealed that both compounds regulated local gene expression. Vitamin E reduced androgen signaling without affecting androgen metabolism. Lycopene interfered with local testosterone activation by down-regulating 5-alpha-reductase and consequently reduced steroid target genes expression (cystatin-related protein 1 and 2, prostatic spermine binding protein, prostatic steroid binding protein C1, C2 and C3 chain, probasin). In addition, lycopene down-regulated prostatic IGF-I and IL-6 expression. Based on these findings, we suggest that lycopene and vitamin E contribute to the reduction of prostate cancer by interfering with internal autocrine or paracrine loops of sex steroid hormone and growth factor activation/synthesis and signaling in the prostate.

Androgens↗
PubMed2006

A transport mechanism for NAADP in a rat basophilic cell line.

NAADP is a second messenger that releases Ca2+ from intracellular stores. Surprisingly, it has been recently shown that extracellular application of NAADP is capable of inducing intracellular Ca2+ release. This is particularly important since the only mammalian enzymes known to catalyze the synthesis of this second messenger are located extracellularly. In the present manuscript, we have investigated whether mammalian cells possess a transport system capable of transporting this highly charged molecule into cells. Indeed, in RBL-2H3 cells, a rat basophilic cell line, and in SK-N-BE cells, a neuroblastoma cell line, [32P]NAADP is efficiently transported inside cells. NAADP transport is Na+ and Ca2+ dependent, is partially blocked by dipyridamole, but is unaffected by nitrobenzylthioinosine. RBL-2H3 cells also transport [32P]cADPR, but the differences in the pharmacological profile suggest that NAADP transport proceeds by a novel mechanism. Lastly, extracellular application of NAADP, but not NADP, induced a raise in intracellular Ca2+. This is the first demonstration that NAADP is transported into cells and highlights the possibility that, alongside a second messenger, NAADP might also act as an autocrine/paracrine signal.

Animals↗
PubMed1998

Autocrine growth stimulation as a potential source of asymmetry in melanocytic skin tumors.

The presence of asymmetry is a major diagnostic criterion for the differentiation of melanoma from benign melanocytic proliferations. It is helpful in both clinical and histological evaluation. The underlying biological features that determine asymmetry have not yet been evaluated. Using computer simulation of the growth of neoplasms, we demonstrate that a functionally homogeneous cell population can give rise to asymmetric lesions when the cells respond to autocrine growth signals. In contrast, neoplastic cells that depend on paracrine stimuli tend to form symmetric lesions. Since the progression of melanocytic neoplasms has been demonstrated to be accompanied by increasing independence of paracrine growth signals and the development of autocrine loops, autocrine growth stimulation has to be considered as a potential source of asymmetry in melanoma.

Autocrine Communication↗
PubMed2000

Biology of hypertensive cardiopathy.

Available data suggest that hypertensive cardiopathy is principally determined by the phenoconversion that allows the myocyte to adapt to the new working conditions by re-expressing a fetal program. Nevertheless, in clinical conditions, the scheme is different. The above phenotype is modified by trophic factors, which originate from ischemia, senescence, diabetes, genetics, or neurohormonal reactions. This review only focuses on some of the most recent advances concerning the permanent changes in the myocyte. Changes in extracellular matrix have been excluded. Recently, emphasis has been on the kinetic basis of the myocardial dysfunction at the myosin level, the potential therapeutic utilization of transferring the adrenergic receptor gene, the participation of NO synthases in the adaptational process, the existence of an abnormal excitation-contraction coupling due to a redistribution of Ca2+ sparks, the role of the microtubule as a determinant of sarcomere motion, and the multifactorial origin of cell death by apoptosis.

Adenosine Triphosphate↗
PubMed1999

Autocrine loops, signal transduction, and cell cycle abnormalities in the molecular biology of lung cancer.

Lung cancers produce a variety of mitogenic neuropeptides and growth factors and express receptors for these signaling peptides leading to autocrine and paracrine loops that stimulate tumor cell proliferation and migration and promote neovascularization. The effects of these autocrine and paracrine factors are mediated by a variety of intracellular signal transduction pathways that ultimately converge on the regulation of cell cycle proteins whose expression and activity are abnormal in lung cancer cells. During the past year, further advances have been made in unraveling autocrine loops, signal transduction pathways, and cell cycle abnormalities in both small cell lung carcinoma (SCLC) and in non-SCLC. In addition, the hunt for novel tumor suppressor genes has continued. As our understanding of the fundamental cell and molecular biology of lung cancer increases, novel possibilities for translational research are emerging for improving the diagnosis, prognosis, and treatment of the disease.

Autocrine Communication↗
PubMed1997

Predicted acetylcholine layer around embryonic motoneurones.

The secretion of acetylcholine (ACh) from cultures of dissociated rat purified embryonic motoneurones into the medium was measured at different times using a chemiluminescent assay. From these results it is proposed that a motoneurone is able to generate an extracellular ACh layer surrounding its membrane. This layer is expected to modulate the ACh concentration at the membrane in a range where ACh receptors can be sensitive, and thus to affect the response of the motoneurone. The influences of both membrane-bound and soluble-secreted acetylcholinesterase (AChE) were simulated and a local ACh membrane efflux was deduced. Since ACh usually exerts an inhibitory effect on neurite outgrowth, a possible autocrine influence of the ACh layer in motoneurone morphogenesis is discussed.

Acetylcholine↗
PubMed2000

Endogenous APP derivatives oppositely modulate apoptosis through an autocrine loop.

We have recently shown that, in rat cerebellar granule cells, apoptosis triggered by KCl deprivation is associated with an amyloidogenic shift in the processing of amyloid precursor protein (APP) resulting in an increase of amyloid beta-protein (A beta) secretion. To further investigate this issue we studied the relationship between secretion of APP metabolites (A beta, APPs) and neuronal degeneration. We postulated that the endogenous products of the APP metabolism may modulate neuronal survival by an autocrine loop. Treatment of cerebellar granule cells with various antibodies raised against different epitopes of APPs and A beta oppositely modulates low potassium apoptotic cell death. Antibodies specific for the N-terminal of A beta (4G8, 6E10, R3659) increased neuronal survival by 30% over controls. On the contrary, treatment of cultures undergoing apoptosis with the monoclonal antibody 22C11 directed against the APP N-terminus reduced neuronal survival by 53%, suggesting that endogenous alpha-APPs contribute to neuronal survival. Moreover low KCl culture medium, conditioned by cerebellar granule cells, attenuated the apoptotic process. This anti-apoptotic effect was abolished by removal of APPs from the conditioned medium. Western blotting of APPs removed from the conditioned medium confirmed the presence of alpha-APPs. These data indicate that APP cleavage products oppositely modulate neuronal survival through an autocrine loop and further strengthen an Alzheimer's disease pathogenetic scheme based on altered metabolism of APP.

Amyloid beta-Protein Precursor↗
PubMed2001

Calpain inhibitors prevent nitric oxide-triggered excitotoxic apoptosis.

The pathogenesis of some neurodegenerative disorders has been linked to excitotoxicity, excess generation of nitric oxide (NO) and apoptosis. Here, we used a model of NO-triggered neuronal apoptosis that was strictly dependent on autocrine NMDA receptor (NMDA-R) activation and intracellular Ca2+ increase. We investigated the efficiency and potentially beneficial effects of calpain inhibition. Three calpain inhibitors that prevented intracellular fodrin proteolysis also blocked apoptotic features such as decrease in mitochondrial membrane potential, chromatin breakdown, and subsequent death of cerebellar granule neurons exposed to NO donors (S-nitroso-L-glutathione, S-nitroso-N-acetyl-d,l-penicillamine, and diethylamino-diazenolate-2-oxide). Since inhibitors did not interfere with NMDA-R activation, we suggest that block of calpains blunts NO-triggered neuronal apoptosis by stopping the cascade downstream of primary autocrine excitotoxic events.

Animals↗
PubMed2001

Adrenomedullin regulates blood-brain barrier functions in vitro.

Adrenomedullin (AM) is an important vasodilator in cerebral circulation, and cerebral endothelial cells are a major source of AM. This in vitro study aimed to determine the AM-induced changes in blood-brain barrier (BBB) functions. AM administration increased, whereas AM antisense oligonucleotide treatment decreased transendothelial electrical resistance. AM incubation decreased BBB permeability for sodium fluorescein (mol. wt 376 Da) but not for Evan's blue albumin (mol. wt 67 kDa), and it also attenuated fluid-phase endocytosis. AM treatment resulted in functional activation of P-glycoprotein efflux pump in vitro. Our results indicate that AM as an autocrine mediator plays an important role in the regulation of BBB properties of the cerebral endothelial cells.

Adrenomedullin↗
PubMed2004

Ca(v)3.2 calcium channels control an autocrine mechanism that promotes neuroblastoma cell differentiation.

Calcium influx via low-voltage activated alpha(1H) (Ca(v)3.2) T-currents participates in the morphological and electrical differentiation of neuroblastoma NG108-15 cells. We investigated whether an autocrine mechanism could contribute to this differentiation process. The presence of factors secreted by NG108-15 cells was identified through the use of conditioned media (CM) obtained from differentiated cells. These CM significantly increased neuritogenesis with no change in the HVA calcium channel expression. CM-induced neuritogenesis persists during alpha(1H) current block, whereas CM obtained from cells transfected with an alpha(1H) antisense did not induce neuritogenesis. These data indicate that morphological differentiation of NG108-15 cells depends on an autocrine mechanism, which is controlled by alpha(1H) currents. Such a mechanism is likely to play a role in the various differentiation processes that imply alpha(1H) T-type Ca(2+) channels.

Animals↗
PubMed2004

Interleukin-10 expression in lipopolysaccharide-activated microglia is mediated by extracellular ATP in an autocrine fashion.

Immune cells have been shown to release ATP into the extracellular space to provide auto- and paracrine purinergic modulation of immune and inflammatory responses. In the present study, we demonstrate that ATP released from lipopolysaccharide (LPS)-stimulated microglia induces interleukin-10 (IL-10) expression in an autocrine manner. The expression as well as secretion of IL-10 by LPS-stimulated microglia was completely inhibited by apyrase, ATP-hydrolyzing enzyme, whereas tumor necrosis factor-alpha (TNF-alpha) expression was unaffected. LPS-activated microglia rapidly released a low concentration of ATP (10-20 nM) into the medium, and the nanomolar range of extracellular ATP, ADP, adenosine 5'-O-(3-thiotriphosphate) (ATP-gamma-S), and adenosine 5'-O-(2-thiodiphosphate) (ADP-beta-S) induced IL-10 secretion from microglia in a dose-dependent manner. These results suggest that ATP released from LPS-activated microglia and/or a metabolite of ATP (ADP) may induce IL-10 expression through P2Y purinergic receptors.

Adenosine Triphosphate↗
PubMed2002

Autocrine and/or paracrine insulin-like growth factor-I activity in skeletal muscle.

Similar to bone, skeletal muscle responds and adapts to changes in loading state via mechanisms that appear to be intrinsic to the muscle. One of the mechanisms modulating skeletal muscle adaptation it thought to involve the autocrine and/or paracrine production of insulinlike growth factor-I. This brief review outlines components of the insulinlike growth factor-I system as it relates to skeletal muscle and provides the rationale for the theory that insulinlike growth factor-I is involved with muscle adaptation.

1-Phosphatidylinositol 4-Kinase↗