Dendritic cells (DC) are highly motile and play a key role in mediating immune responses in various tissues and lymphatic organs. We investigated locomotion of mononuclear cell-derived DC at different maturation stages toward gradients of sensory neuropeptides in vitro. Calcitonin gene-related peptide, vasoactive intestinal polypeptide, secretin, and secretoneurin induced immature DC chemotaxis comparable to the potency of RANTES, whereas substance P and macrophage-inflammatory protein-3beta stimulated immature cell migration only slightly. Checkerboard analyses revealed a true chemotactic response induced by neuropeptides. Upon maturation of DC, neuropeptides inhibited spontaneous, macrophage-inflammatory protein-3beta- and 6Ckine-induced cell migration. Maturation-dependent changes in migratory behavior coincided with distinct neuropeptide-induced signal transduction in DC. Peripheral neuropeptides might guide immature DC to peripheral nerve fibers where high concentrations of these peptides can arrest the meanwhile matured cells. It seems that one function of sensory nerves is to fasten DC at sites of inflammation. (+info)
Secretoneurin and neurogenic inflammation.
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AIM: Review of evidence that the 33-amino-acid polypeptide secretoneurin, which is generated by proteolytic cleavage of secretogranin II, plays a role in neurogenic inflammation. METHODS: Survey of the literature using a MEDLINE search database. RESULTS: Secretoneurin is synthesized in spinal ganglia, transported through the dorsal roots and stored in the axon terminals of primary afferent neurons. Investigations using capsaicin suggest that secretoneurin functions as an excitatory transmitter. Secretoneurin specifically activates various cell functions including the chemotactic migration of monocytes, eosinophils, fibroblasts, smooth muscle cells, and endothelial cells, which suggests that the peptide may modulate inflammatory reactions. Secretoneurin receptors have been functionally characterized. They are G-proteins linked and effects are abrogated by inhibition of protein kinase C. CONCLUSION: With actions as diverse as those seen with other mediators such as tachykinins, secretoneurin may be considered another sensory neuropeptide with modulatory potential in neurogenic inflammation. (+info)
Pituitary adenylate cyclase-activating polypeptide stimulates secretoneurin release and secretogranin II gene transcription in bovine adrenochromaffin cells through multiple signaling pathways and increased binding of pre-existing activator protein-1-like transcription factors.
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Secretoneurin (SN) is a novel bioactive peptide that derives from the neuroendocrine protein secretogranin II (SgII) by proteolytic processing and participates in neuro-immune communication. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP-38) dose-dependently stimulates (EC(50) approximately 3 nM) SN release (up to 4-fold) and SgII gene expression (up to 60-fold) in cultured bovine adrenochromaffin cells. The effect of PACAP on both SN secretion and SgII mRNA levels is rapid and long lasting. We analyzed in this neuroendocrine cell model the transduction pathways involved in both SN secretion and SgII gene transcription in response to PACAP. The cytosolic calcium chelator BAPTA-AM and the nonselective calcium channel antagonist NiCl(2) equally inhibited both secretion of the peptide and transcription of the SgII gene, indicating a major contribution of calcium influx in PACAP-induced SN biosynthesis and release in chromaffin cells. Inhibition of protein kinase A (PKA) or C (PKC) also reduced PACAP-evoked SN release but did not alter the stimulatory effect of PACAP on SgII mRNA levels. Conversely, application of mitogen-activated protein kinase inhibitors suppressed PACAP-induced SgII gene expression. The effect of PACAP on SgII mRNA levels, like the effect of the PKC stimulator 12-O-tetradecanoylphorbol-13-acetate (TPA), was not affected by cycloheximide, whereas the effects of the PKA stimulator forskolin or cell-depolarization by high K(+) were significantly reduced by the protein synthesis inhibitor. PACAP and TPA both increased the binding activity of the SgII cAMP response element to trans-acting factors present in chromaffin cell nuclear extracts, which are recognized by antibodies to activator protein-1-related proteins. These data indicate that SN biosynthesis is regulated by PACAP in chromaffin cells through complex signaling cascades, suggesting that SN may play a function during trans-synaptic stimulation of the adrenal medulla. (+info)
Inhibitory effect of certain neuropeptides on the proliferation of human retinal pigment epithelial cells.
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AIMS: To define the effect of the neuropeptides substance P, calcitonin gene related peptide, vasoactive intestinal polypeptide, neuropeptide Y, and secretoneurin on the proliferation of human retinal pigment epithelial (RPE) cells. METHODS: ARPE-19 cells were used. The cells were cultured in Dulbecco's modified Eagle's medium. 1000 and 2000 cells were incubated with the peptides for 3 and 5 days, and the effect of the peptides was evaluated by an ATP lite assay dose dependently. Furthermore, specific antagonists at 10(-6) M were used to find out whether the effect would be reversed. RESULTS: In brief, each of the peptides tested had an inhibiting effect. This inhibiting effect was weak but highly significant, averaging 10% to 15%, and was most pronouncedly seen at concentrations between 10(-10) M and 10(-14) M. Each antagonist reversed the inhibiting effect fully. CONCLUSIONS: These results clearly indicate that RPE cells are under neural control and the low effective concentration of the peptides may be the one physiologically acting on these cells. The results are of important relevance both physiologically and pathophysiologically: physiologically, the inhibitory effect may mean that these peptides cause the cells to remain in a differentiated condition. Pathophysiologically, the findings are relevant in proliferative vitreoretinopathy where RPE cells proliferate in excess. The authors hypothesise that the inhibiting effect diminishes when these cells are swept out and actively migrate from their physiological location and thus, dedifferentiate and begin to proliferate. This hypothesis improves the knowledge of the initial processes in the pathogenesis of the disease as there seems to be a discrepancy between facilitatory and inhibitory influences favouring the former in proliferative vitreoretinopathy. Furthermore, these neuropeptides constitute the first endogenous inhibitors of RPE cell proliferation. (+info)
The neuropeptide secretoneurin acts as a direct angiogenic cytokine in vitro and in vivo.
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BACKGROUND: Secretoneurin is an abundant neuropeptide of the central, peripheral, and autonomic nervous systems, located in nerve fibers characterized by a close interaction with blood vessels and known to stimulate endothelial cell migration. METHODS AND RESULTS: We hypothesized that secretoneurin might act as an angiogenic cytokine and tested for these effects in vivo using a mouse cornea neovascularization model and in vitro by assessing capillary tube formation in a matrigel assay. In vivo, secretoneurin-induced neovasculature is characterized by a distinct pattern of arterial and venous vessels of large diameter and length. Immunohistochemical staining for CD-31 revealed endothelial lining of the inner surface of these vessels, and recruitment of alpha-smooth muscle actin-positive perivascular cells suggests vessel maturation. In vitro, secretoneurin-induced capillary tube formation was dose dependent and specific, confirming that effects of secretoneurin occur directly on endothelial cells. Secretoneurin also stimulated proliferation and exerted antiapoptotic effects on endothelial cells and activated intracellular phosphatidylinositol 3' kinase/Akt and mitogen-activated protein kinase pathways, as demonstrated by increased phosphorylation of Akt and extracellular signal-regulated kinase. CONCLUSIONS: These data show that secretoneurin represents a novel direct angiogenic cytokine and reiterate the coordinated relationship between nervous and vascular systems. (+info)
The immune modulator FTY720 targets sphingosine-kinase-dependent migration of human monocytes in response to amyloid beta-protein and its precursor.
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Accumulation of inflammatory mononuclear phagocytes in Alzheimer's senile plaques, a hallmark of the innate immune response to beta-amyloid fibrils, can initiate and propagate neurodegeneration characteristic of Alzheimer's disease. Phagocytes migrate toward amyloid beta-protein involving formyl peptide receptor like-1-dependent signaling. Using human peripheral blood monocytes in Boyden chamber micropore filter assays, we show that the amyloid beta-protein- and amyloid beta-precursor protein-induced migration was abrogated by dimethylsphingosine, a sphingosine kinase inhibitor. Amyloid beta-protein stimulated in monocytes the gene expression for sphingosine-1-phosphate receptors 2 and 5, but not 1, 3, and 4. FTY720 that acts as a sphingosine-1-phosphate receptor agonist after endogenous phosphorylation by sphingosine kinase, as well as various neuropeptides that are known to be monocyte chemoattractants, dose-dependently inhibited amyloid beta-protein-induced migration. These data demonstrate that the migratory effects of beta-amyloid in human monocytes involve spingosine-1-phosphate signaling. Whereas endogenous neuropeptides may arrest and activate monocytes at sites of high beta-amyloid concentrations, interference with the amyloid beta-protein-dependent sphingosine-1-phosphate pathway in monocytes by FTY720, a novel immunomodulatory drug, suggests that FTY720 may be efficacious in beta-amyloid-related inflammatory diseases. (+info)
Secretoneurin, an angiogenic neuropeptide, induces postnatal vasculogenesis.
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BACKGROUND: Induction of postnatal vasculogenesis, the mobilization of bone marrow-derived endothelial progenitor cells and incorporation of these cells into sites of blood vessel formation, is a well-known feature of angiogenic cytokines such as vascular endothelial growth factor. We hypothesized that the angiogenic neuropeptide secretoneurin induces this kind of neovascularization. METHODS AND RESULTS: Secretoneurin induced mobilization of endothelial progenitor cells to sites of vasculogenesis in vivo in the cornea neovascularization assay. Progenitor cells were incorporated into vascular structures or were located adjacent to them. Systemic injection of secretoneurin led to increase of circulating stem cells and endothelial progenitor cells. In vitro secretoneurin induced migration, exerted antiapoptotic effects, and increased the number of these cells. Furthermore, secretoneurin stimulated the mitogen-activated protein kinase system, as shown by phosphorylation of extracellular signal-regulated kinase, and activated the protein kinase B/Akt pathway. Activation of mitogen-activated protein kinase was necessary for increase of cell number and migration, whereas Akt seemed to play a role in migration of endothelial progenitor cells. CONCLUSIONS: These data show that the angiogenic neuropeptide secretoneurin stimulates postnatal vasculogenesis by mobilization, migration, and incorporation of endothelial progenitor cells. (+info)
Secretoneurin in the peripheral ocular innervation.
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PURPOSE: To evaluate whether secretoneurin represents a sensory neuropeptide innervating the anterior segment of the eye. METHODS: The presence and distribution of secretoneurin was investigated in human eyes by radioimmunoassay and immunofluorescence and compared with that of the rat eye. The source of secretoneurin-positive nerves in the eye was established by measuring the concentration in eye tissues, the trigeminal and superior cervical ganglia both in control rats and in rats treated with capsaicin, and by performing immunofluorescence in one rat subjected to sympathectomy. In the rat trigeminal ganglion, the corresponding mRNA was verified by in situ hybridization and the processing of secretogranin II into secretoneurin by gel filtration chromatography. RESULTS: In human eyes, the highest levels of the peptide were found in the choroid. Nerve fibers were visualized in both species in the upper corneal and limbal stroma; in the trabecular meshwork; in the ciliary muscle, the ciliary body stroma, and processes; and in clear association with the dilator muscle, which disappeared after sympathetic denervation in rats; and also innervating the sphincter muscle in the iris and the choroidal stroma and surrounding blood vessels. Significant amounts of secretoneurin were present in the rat trigeminal ganglion and rat eye tissues. Capsaicin pretreatment led to a 57.0% +/- 4.3% and 59.1% +/- 11.9% decrease of the concentration in the trigeminal ganglion and the iris/ciliary body complex, respectively. Despite high levels in the rat superior cervical ganglion, sympathetic denervation failed to lower the concentration in eye tissues. The secretogranin II probe labeled numerous small-sized ganglion cells within the rat trigeminal ganglion, and the precursor of the peptide was found to become completely processed into secretoneurin. CONCLUSIONS: Apart from the sympathetically innervated dilator muscle, there is unequivocal evidence that secretoneurin represents a constituent of capsaicin-sensitive sensory neurons in the rat trigeminal ganglion and of unmyelinated C-fibers in the rat iris/ciliary body complex, which indicates a participation of this peptide in the ocular irritative response, a model for neurogenic inflammation in lower mammals. Because of the association of nerves with blood vessels and potent angiogenic properties, secretoneurin may be involved in neovascularization processes. (+info)