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At least 757 records · Page 42Linked to original sources
PubMed2002

Corticotropin-releasing hormone signaling in synovial tissue vascular endothelium is mediated through the cAMP/CREB pathway.

Modulation of locally produced corticotropin-releasing hormone (CRH) is a component of the cytokine network in human inflammatory arthritis. CRH signaling, through the CRH-receptor subtype R1alpha, may play a role in both vascular changes and pathologic mechanisms associated with joint inflammation. Furthermore, the peripheral actions of CRH may be mediated in part through the NURR subfamily of nuclear orphan receptors. The aim of this study was to establish the signaling mechanisms through which CRH receptor-mediated responses contribute to gene regulation in inflamed synovial vasculature. Immunohistochemical analysis of serial rheumatoid arthritis (RA) tissue sections demonstrates CRH and NURR1 expression in the synovial lining layer, subsynovial lining layer, and the vascular endothelium. The identical pattern of immunolocalization confirms that NURR1 is produced at the same synovial sites shown to produce CRH. The distribution of specific NURR1 staining on the synovial vasculature parallels that observed for CRH-R1 expression. Using primary synovial tissue endothelial cells, we demonstrate that CRH induces specific CREB-1 and ATF-2 binding to the NURR1 promoter. We further provide evidence that CRH signaling can be mimicked by activation of cAMP/PKA/CREB using forskolin in primary human microvascular endothelial cells. These data indicate that the CRH receptor-dependent inflammatory response in synovial tissue endothelium is mediated through the cAMP/CREB signaling pathway.

Active Transport, Cell Nucleus↗
PubMed2003

Avian melanocortin system: alpha-MSH may act as an autocrine/paracrine hormone: a minireview.

The interest in the physiological role of alpha-MSH in birds has been limited because they lack the intermediate lobe of the pituitary, the main source of circulating alpha-MSH in most vertebrates. Recent studies have improved our understanding of the avian melanocortin system. We have cloned and characterized all five MC-R subtypes, POMC, and AGRP in chicken. Analyses of the tissue distribution of expression of these genes revealed widespread expression throughout the body, corresponding to the situation in mammals in which alpha-MSH exerts a multiplicity of effects in different tissues by acting as a local mediator. We showed that the extended black locus controlling feather pigmentation in the chicken encodes MC1-R. Moreover, black chickens carrying the dominant allele, the extended black, express the MC1-R with ligand-independent activity as the somber-3J black mice. alpha-MSH and AGRP were expressed in the infundibular nucleus of POMC and NPY neurons, respectively, in the brain of Japanese quail. Furthermore, fasting stimulated AGRP expression and lowered POMC expression. These data indicate that at least two of the major melanocortin systems reported in mammals, that is, regulation of pigmentation and energy homeostasis, was developed in a common ancestor to chicken and mammals at least 300 million years ago. Furthermore, alpha-MSH peptide was identified in developing chicken eye, suggesting a possible involvement of alpha-MSH in regulation of ocular development. Collectively, the data reviewed here indicate that alpha-MSH is produced locally and acts as an autocrine/paracrine hormone in birds.

Animals↗
PubMed2003

New models to investigate mechanisms of disease genesis from primitive BCR-ABL(+) hematopoietic cells.

Three years ago we described a novel autocrine IL-3/G-CSF mechanism active in the leukemic CD34(+) cells from chronic myeloid leukemia (CML) patients in chronic phase (PNAS 96: 12804-12809, [1999]). We also showed that exposure of the most primitive CD34(+) cells from normal human bone marrow to excess IL-3 stimulates not only the division of these cells but also their differentiation. In contrast, both IL-3 and G-CSF cause an expansion of the more mature types of normal CD34(+) progenitors. These findings suggested that the autocrine IL-3/G-CSF mechanism active in CML stem cells can compromise their self-renewal in spite of increasing their proliferative activity, which, in turn, might explain the paradoxically slow rate of expansion of this compartment over time in patients with latent disease. To investigate this hypothesis, we have begun to characterize the numbers and types of cells generated from chronic phase CML patients' cells transplanted into adult immunodeficient mice or fetal sheep, and also from transplants of primitive murine and human hematopoietic cells transduced with a retroviral BCR-ABL vector. Our findings to date using these models reinforce the importance of the autocrine IL-3/G-CSF mechanism in the development of CML. BCR-ABL appears to directly activate IL-3 and G-CSF production in primitive hematopoietic cells and this is important to their transplantable leukemogenic activity. However, the development in vivo of an overt leukemia from primitive BCR-ABL(+) hematopoietic cells can be very delayed. These models thus offer new opportunities for analyzing the molecular events that underlie the pathogenesis of human CML and the future testing of new therapeutic approaches.

Animals↗
PubMed2003

Presynaptic modulation of rat arterial chemoreceptor function by 5-HT: role of K+ channel inhibition via protein kinase C.

The peripheral control of breathing is mediated by O2-sensitive carotid body (CB) type 1 cells, which express multiple neurotransmitters including the monoamines, dopamine and serotonin (5-HT). Whereas dopamine has been extensively studied, 5-HT has received little attention. Here, to elucidate the role of 5-HT in CB chemotransmission, we used perforated-patch recording from rat type 1 cell clusters and co-cultured petrosal (afferent) neurones. 5-HT induced action potentials and/or membrane depolarization associated with a conductance decrease in approximately 40% of recordings from type 1 cells (n = 78/192). These responses were markedly inhibited by the 5-HT2 receptor antagonist ketanserin (10-50 microM) and by the protein kinase C (PKC) inhibitor chelerythrine (50 microM). The PKC activator 1-oleoyl-2-acetylglycerol (OAG; 50 microM) mimicked the 5-HT-induced depolarization, and the combined effects of 5-HT and OAG were non-additive. The 5-HT-induced responses reversed near the potassium (K+) equilibrium potential (at approximately -82 mV; EK = -83 mV), suggesting inhibition of a resting K+ conductance. In type 1 cells (n = 7), voltage-activated outward K+ current was also inhibited by 1-50 microM 5-HT, an effect that was prevented by PKC inhibitors (chelerythrine and NPC 15437) and mimicked by OAG; the outward K+ current inhibited by 5-HT appeared to be predominantly a Ca(2+)-dependent K+ current. The 5-HT2 receptor blockers ketanserin and ritanserin reversibly inhibited spontaneous action potentials and the hypoxia-induced receptor potential recorded from clustered type 1 cells. Moreover, these blockers reversibly inhibited the hypoxic chemosensory response recorded postsynaptically in petrosal neurones that functionally innervated type 1 clusters in co-culture. RT-PCR and confocal immunofluorescence techniques revealed 5-HT2a receptor expression in rat CB type 1 cells. These results suggest that release of endogenous 5-HT regulates CB chemoreceptor function presynaptically, by a positive feedback mechanism involving autocrine-paracrine stimulation of 5-HT2a receptors and PKC modulation of resting and Ca(2+)-dependent K+ conductances.

Animals↗
PubMed2004

Autocrine feedback inhibition of plateau potentials terminates phasic bursts in magnocellular neurosecretory cells of the rat supraoptic nucleus.

Phasic activity in magnocellular neurosecretory cells is characterized by alternating periods of activity (bursts) and silence. During phasic bursts, action potentials are superimposed on plateau potentials that are generated by summation of depolarizing after-potentials. Dynorphin is copackaged in vasopressin neurosecretory vesicles that are exocytosed from magnocellular neurosecretory cell dendrites and terminals, and both peptides have been implicated in the generation of phasic activity. Here we show that somato-dendritic dynorphin release terminates phasic bursts by autocrine inhibition of plateau potentials in magnocellular neurosecretory cells recorded intracellularly from hypothalamic explants using sharp electrodes. Conditioning spike trains caused an activity-dependent reduction of depolarizing after-potential amplitude that was partially reversed by alpha-latrotoxin (which depletes neurosecretory vesicles) and by nor-binaltorphimine (kappa-opioid receptor antagonist), but not by an oxytocin/vasopressin receptor antagonist or a micro-opioid receptor antagonist, indicating that activity-dependent inhibition of depolarizing after-potentials requires exocytosis of an endogenous kappa-opioid peptide. kappa-Opioid inhibition of depolarizing after-potentials was not mediated by actions on evoked after-hyperpolarizations since these were not affected by kappa-opioid receptor agonists or antagonists. Evoked bursts were prolonged by antagonism of kappa-opioid receptors with nor-binaltorphimine and by depletion of neurosecretory vesicles by alpha-latrotoxin, becoming everlasting in approximately 50% of cells. Finally, spontaneously active neurones exposed to nor-binaltorphimine switched from phasic to continuous firing as plateau potentials became non-inactivating. Thus, dynorphin coreleased with vasopressin generates phasic activity through activity-dependent feedback inhibition of plateau potentials in magnocellular neurosecretory cells.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2004

Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain.

Oxytocin is released from supraoptic magnocellular neurones and is thought to act at presynaptic receptors to inhibit transmitter release. We now show that this effect is mediated by endocannabinoids, but that oxytocin nonetheless plays an important role in endocannabinoid signalling. WIN55,212-2, a cannabinoid receptor agonist, mimicked the action of oxytocin and occluded oxytocin-induced presynaptic inhibition. The cannabinoid action is at the presynaptic terminal as shown by alteration in paired pulse ratio, a reduction in miniature EPSC frequency and immunohistochemical localization of CB1 receptors on presynaptic terminals. AM251, a CB1 receptor antagonist, blocked both the WIN55,212-2 and the oxytocin-induced presynaptic inhibition of EPSCs. Depolarization of postsynaptic magnocellular neurones (which contain fatty acid amide hydrolase, a cannabinoid catabolic enzyme) caused a transient inhibition of EPSCs that could be blocked by both the AM251 and Manning compound, an oxytocin/vasopressin receptor antagonist. This indicates that somatodendritic peptide release and action on previously identified autoreceptors facilitates the release of endocannabinoids that act as mediators of presynaptic inhibition.

Animals↗
PubMedDate not supplied

Shear stress induction of C-type natriuretic peptide (CNP) in endothelial cells is independent of NO autocrine signaling.

C-type natriuretic peptide (CNP) is secreted by endothelial cells and has vasodilatory and antiproliferative activity against smooth muscle cells. Using defined laminar shear stress exposures of cultured bovine aortic endothelial cells, we investigated the regulation of CNP gene by PhosphorImaging the ratio of CNP mRNA to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA. A 6 h exposure to arterial shear stress of 25 dyn/cm2 caused a marked elevation (10.5 +/- 6.2-fold: n=10, p<0.001) of CNP/GAPDH mRNA ratio compared to stationary controls. Arterial shear stress was 2.6 times more potent than a venous level of shear stress of 4 dyn/cm2 in elevating the CNP/GAPDH mRNA ratio. After 6 h, CNP secretion by shear stressed BAEC was elevated over stationary controls by 3.1-fold (n=5, p<0.001) to a level of 34 +/- 7.5 pg/cm2 BAEC. Shear stress elevated CNP mRNA in the presence of L-NAME (400 microM) indicating that autocrine signaling through shear-induced NO production or guanylate cyclase activation was not involved. Similarly, the tyrosine kinase inhibitor genistein (10 microM), which can also block shear-induced NO production, had no effect on CNP mRNA induction by shear stress in BAEC. The intracellular calcium chelator BAPTA/AM (5 microM) attenuated the shear stress-induced CNP mRNA expression by 71%. Interestingly, dexamethasone (1 microM) potentiated by 2-fold the shear stress enhancement of CNP mRNA. Shear stress was a more potent inducer of CNP than either phorbol myristrate acetate or lipopolysaccharide. Hemodynamic shear stress may be an important physiological regulator of CNP expression with consequent effects on vasodilation and regulation of intimal hyperplasia.

Animals↗
PubMed2004

A model for mechanotransduction in cardiac muscle: effects of extracellular matrix deformation on autocrine signaling.

We present a computational model and analysis of the dynamic behavior of epidermal growth factor receptor (EGFR) signaling in cardiac muscle tissue, with the aim of exploring transduction of mechanical loading into cellular signaling that could lead to cardiac hypertrophy. For this purpose, we integrated recently introduced models for ligand dynamics within compliant intercellular spaces and for the spatial dynamics of intracellular signaling with a positive feedback autocrine circuit. These kinetic models are here considered in the setting of a tissue consisting of cardiomyocytes and blood capillaries as a structural model for the myocardium. We show that autocrine EGFR signaling can be induced directly by mechanical deformation of the tissue and demonstrate the possibility of self-organization of signaling that is anisotropic on the tissue level and can reflect anisotropy of the mechanical deformation. These predictions point to the potential capabilities of the EGFR autocrine signaling circuit in mechanotransduction and suggest a new perspective on the cardiac hypertrophic response.

Animals↗
PubMed2004

A novel benzodiazepine selectively inhibits keratinocyte proliferation and reduces retinoid-induced epidermal hyperplasia in organ-cultured human skin.

Bz-423 is a new benzodiazepine that has cytotoxic and cytostatic effects against a number of cell types in culture, and recent studies have shown efficacy in experimental lupus models in rodents. The present study demonstrates that treating human skin in organ culture with Bz-423 suppresses retinoid-induced epidermal hyperplasia. Bz-423 suppresses hyperplasia in organ culture at concentrations that also inhibit keratinocyte proliferation in monolayer culture but that are not cytotoxic for keratinocytes and do not inhibit fibroblast growth. Under conditions in which keratinocyte proliferation is inhibited, there is no measurable effect on epidermal growth factor receptor activation, but there is reduced signaling at the level of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase. Suppression of keratinocyte growth by Bz-423 is associated with generation of intracellular oxidants. However, antioxidant treatment reduces keratinocyte cytotoxicity that occurs at high concentrations of Bz-423, but it does not inhibit growth suppression. Together, these data suggest that Bz-423 has the potential to limit the untoward effects associated with topical retinoid treatment, and in addition, may have therapeutic effects against other forms of epidermal hyperplasia.

Autocrine Communication↗
PubMed2004

Tumor necrosis factor-alpha differentially regulates the expression of proinflammatory genes in human airway smooth muscle cells by activation of interferon-beta-dependent CD38 pathway.

Recent evidence suggests that CD38, an ectoenzyme that converts NAD(+) to cyclic ADP-ribose (cADPr), may play a role in cytokine-induced airway smooth muscle (ASM) cell hyper-responsiveness, a key feature associated with chronic asthma. In the present study, we investigated the major signaling pathways by which tumor necrosis factor-alpha (TNFalpha) induces CD38 expression and its role in regulating gene expression in human ASM cells. Using flow cytometry analyses, TNFalpha enhanced CD38 expression in a manner that was time-(0-24 h), concentration-(0.1-40 ng/ml), and protein synthesis-(cycloheximide blockade) dependent. A selective agonistic antibody against tumor necrosis factor receptor (TNFR) 1 also augmented CD38 expression, whereas anti-TNFR2 antagonistic antibody did not prevent the TNFalpha response. Inhibition of the Janus activated kinase/signal transducer and activator of transcription pathways using the soluble inhibitor 2-(1,1-dimethylethyl)-9-fluoro-3,6-dihydro-7H-benz-[h]imidaz[4,5-f]isoquinolin-7-one (DBI) or with neutralizing antibody against interferon beta (IFNbeta) completely abrogated TNFalpha-induced CD38 expression at both protein and mRNA levels. Combining TNFalpha (0.1 and 1 ng/ml) and IFNbeta (100 IU/ml) at concentrations alone that had little effect on CD38 expression induced a robust synergistic induction of CD38 mRNA and protein levels. 8-Bromo-cADPr, a cADPr antagonist, significantly augmented TNFalpha-induced interleukin-6 secretion, whereas regulated on activation normal T cell expressed and secreted secretion was suppressed. 8-Bromo-cADPr, however, did not affect TNFalpha-induced cell surface expression of intercellular adhesion molecule-1. Our study is the first to demonstrate that IFNbeta-dependent activation of CD38 pathway is a novel component by which TNFalpha differentially regulates the expression of inflammatory genes in ASM cells.

ADP-ribosyl Cyclase↗
PubMed1999

Activation of leukotriene synthesis in human neutrophils by exogenous arachidonic acid: inhibition by adenosine A(2a) receptor agonists and crucial role of autocrine activation by leukotriene B(4).

We report here that the apparent inability of isolated human polymorphonuclear leukocytes (PMNs) to efficiently transform arachidonic acid (AA) is the consequence of A(2a) receptor engagement by endogenous adenosine accumulating in incubation media. Indeed, when adenosine is eliminated from PMN suspensions by the addition of adenosine deaminase, or when cells are incubated with adenosine A(2a) receptor antagonists, important quantities (40-80 pmol/10(6) cells) of 5-lipoxygenase products are synthesized by PMN incubated with 1 to 5 microM exogenous AA. The selective A(2a) receptor agonist CGS21680 was a very potent inhibitor of the AA-induced leukotriene (LT) synthesis, showing an IC(50) of approximately 1 nM. The mechanism of AA-induced stimulation of LT synthesis observed in the absence of extracellular adenosine was investigated. In adenosine deaminase-treated PMN, exogenous AA induced Ca(2+) mobilization and the translocation of 5-lipoxygenase to nuclear structures. A time lag of 20 to 60 s (variable between PMN preparations) was observed consistently between the addition of AA and the elevation of intracellular Ca(2+) concentration (and LT synthesis), indicating that AA itself did not trigger the Ca(2+) mobilization in PMN. This AA-induced Ca(2+) mobilization, as well as the corresponding 5-lipoxygenase translocation and stimulation of LT synthesis, was blocked efficiently by the LT synthesis inhibitor MK0591, the LTB(4) receptor antagonists CP105696 and LY223982, and the LTA(4) hydrolase inhibitor SC57461A. These data demonstrate that AA is a highly potent and effective activator of LT synthesis and acts through a mechanism that requires an autocrine stimulatory loop by LTB(4).

Adenosine↗
PubMed2001

Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation.

Many hematopoietic cells undergo apoptosis when deprived of specific cytokines, and this process requires de novo RNA/protein synthesis. Using DNA microarrays to analyze interleukin-3 (IL-3)-dependent murine FL5.12 pro-B cells, we found that the gene undergoing maximal transcriptional induction after cytokine withdrawal is 24p3, which encodes a secreted lipocalin. Conditioned medium from IL-3-deprived FL5.12 cells contained 24p3 and induced apoptosis in naive FL5.12 cells even when IL-3 was present. 24p3 also induced apoptosis in a wide variety of leukocytes but not other cell types. Apoptotic sensitivity correlated with the presence of a putative 24p3 cell surface receptor. We conclude that IL-3 deprivation activates 24p3 transcription, leading to synthesis and secretion of 24p3, which induces apoptosis through an autocrine pathway.

Acute-Phase Proteins↗
PubMed2002

Viral IL-6-induced cell proliferation and immune evasion of interferon activity.

Lymphoma cells infected with Kaposi's sarcoma-associated herpesvirus are autocrine dependent on virus-derived interleukin-6 (IL-6), but not on cellular IL-6. During viral infection, host cells induce the antiviral factor interferon (IFN) to up-regulate p21, initiate cell cycle arrest, and inhibit virus replication. Viral IL-6, however, blocks IFN signaling. A viral transcriptional program exists in which only the viral IL-6 gene is directly activated by IFN-alpha, allowing the virus to modify its cellular environment by sensing and responding to levels of intracellular IFN signaling. The human cytokine cannot mimic this effect because IFN-alpha down-regulates the IL-6 receptor, gp80. Viral IL-6 bypasses the gp80 regulatory checkpoint by binding directly to the gp130 transducer molecule, resulting in tumor cell autocrine dependence on the viral cytokine for proliferation and survival.

Antigens, CD↗
PubMed2005

Stimulus specificity of gene expression programs determined by temporal control of IKK activity.

A small number of mammalian signaling pathways mediate a myriad of distinct physiological responses to diverse cellular stimuli. Temporal control of the signaling module that contains IkappaB kinase (IKK), its substrate inhibitor of NF-kappaB (IkappaB), and the key inflammatory transcription factor NF-kappaB can allow for selective gene activation. We have demonstrated that different inflammatory stimuli induce distinct IKK profiles, and we examined the underlying molecular mechanisms. Although tumor necrosis factor-alpha (TNFalpha)-induced IKK activity was rapidly attenuated by negative feedback, lipopolysaccharide (LPS) signaling and LPS-specific gene expression programs were dependent on a cytokine-mediated positive feedback mechanism. Thus, the distinct biological responses to LPS and TNFalpha depend on signaling pathway-specific mechanisms that regulate the temporal profile of IKK activity.

Algorithms↗
PubMed2005

A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis.

Signal transduction pathways control cellular responses to stimuli, but it is unclear how molecular information is processed as a network. We constructed a systems model of 7980 intracellular signaling events that directly links measurements to 1440 response outputs associated with apoptosis. The model accurately predicted multiple time-dependent apoptotic responses induced by a combination of the death-inducing cytokine tumor necrosis factor with the prosurvival factors epidermal growth factor and insulin. By capturing the role of unsuspected autocrine circuits activated by transforming growth factor-alpha and interleukin-1alpha, the model revealed new molecular mechanisms connecting signaling to apoptosis. The model derived two groupings of intracellular signals that constitute fundamental dimensions (molecular "basis axes") within the apoptotic signaling network. Projection along these axes captures the entire measured apoptotic network, suggesting that cell survival is determined by signaling through this canonical basis set.

Apoptosis↗
PubMed2006

ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors.

Cells must amplify external signals to orient and migrate in chemotactic gradient fields. We find that human neutrophils release adenosine triphosphate (ATP) from the leading edge of the cell surface to amplify chemotactic signals and direct cell orientation by feedback through P2Y2 nucleotide receptors. Neutrophils rapidly hydrolyze released ATP to adenosine that then acts via A3-type adenosine receptors, which are recruited to the leading edge, to promote cell migration. Thus, ATP release and autocrine feedback through P2Y2 and A3 receptors provide signal amplification, controlling gradient sensing and migration of neutrophils.

Adenosine↗