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PubMedDate not supplied

Role of progesterone on peri-implantation stage endometrium-embryo interaction in the primate.

Progesterone secretion during the luteal phase influences oviductal and endometrial functions which are essential for embryo viability and implantation in a number of species including primates. Luteal phase estrogen is not essential for progesterone-dependent endometrial receptivity towards implantation and pregnancy in the rhesus monkey and in the human. However, synchronous development of embryo and endometrium is an essential prerequisite for evolutive implantation. Progesterone helps to maintain synchronous development of preimplantation embryo through its action on maternal uterus. The anti-nidatory action of mifepristone, a potent progesterone receptor modulator (PRM) with pronounced antiprogestagenic activity, is known to be associated with desynchronization of endometrium along with repression of glandular secretory differentiation and vascular maturation. Thus, it is likely that early luteal phase administration of mifepristone affects paracrine action of the secretory stage endometrium on the preimplantation stage embryo, and thereby inhibits embryonic development and viability. We shall examine this hypothesis using the rhesus monkey as a primate model.

Animals↗
PubMed2001

Proadrenomedullin-derived peptides in the paracrine control of the hypothalamo-pituitary-adrenal axis.

Adrenomedullin (ADM) and proadrenomedullin N-terminal 20 peptide (PAMP) are widely distributed in various body tissues and organs, including the hypothalamo-pituitary-adrenal (HPA) axis. ADM and PAMP inhibit in vitro release of ACTH from pituitary corticotropes, and findings suggest that this effect may become relevant when an exceedingly high ACTH secretion must be counteracted. ADM directly supresses angiotensin-II- and K+-stimulated aldosterone secretion from ZG cells, acting through calcitonin gene-related peptide (CGRP) type 1 ADM(22-52)-sensitive receptors, the activation of which is likely to impair Ca2+ influx. In contrast, ADM stimulates medullary chromaffin cells to release catecholamines, which in turn enhance aldosterone secretion acting in a paracrine manner. Also this effect of ADM occurs via CGRP1 receptors, which are coupled with the adenylate cyclase-dependent cascade. There is indication that in vivo these two opposite effects of ADM on ZG may interact with each other when normal aldosterone secretion has to be restored. ADM exerts a mitogenic effect on rat ZG, acting via CGRP1 receptors that activate the tyrosine kinase-dependent mitogen-activated protein kinase cascade. These findings, along with the demonstration of a high level of ADM gene expression in adrenocortical adenomas and carcinomas, may suggest a role for ADM as adrenocortical growth stimulator and tumor promoter. PAMP, like ADM, suppresses aldosterone response of ZG cells to Ca2+-dependent agonists, but, in contrast with ADM, it inhibits catecholamine release by adrenal medulla. Both effects of PAMP are mediated by PAMP(12-20)-sensitive receptors, whose signaling mechanism is likely to involve the blockade of voltage-gated Ca2+ channels. The concentrations attained by ADM and PAMP in the blood rule out the possibility that they act as true circulating hormones. Conversely, their content in the hypothalamo-pituitary complex and adrenal gland is consistent with a paracrine mechanism of action, which may play an important role in pathophysiological conditions where the function of the HPA axis has to be reset.

Adrenal Glands↗
PubMed2003

Prostate development and carcinogenesis.

The process involved in the development and carcinogenesis of the prostate gland is complex. During early prostate development, the androgenic hormone from embryonic testicles is required for ductal formation, growth, and branching morphogenesis of the prostate gland. From this early stage, interactions between the epithelium and mesenchyme become firmly established through paracrine influence (i.e., growth factors) from mesenchyme (stroma), in response to testosterone, acting on epithelium to stimulate its proliferation, morphogenetic differentiation, and function. In return, the epithelium also exerts its paracrine effects on mesenchyme by regulating the differentiation and specific organizational pattern of its stromal smooth muscle. In a normal adult prostate, the maintenance of normal glandular structure and function is dependent not only on the constant presence of testosterone, but also on a normal intact and stable stroma. This chapter will concentrate first on factors involved in the normal development of the prostate gland and then on the aberrant changes in the homeostatic balance arising either from within (i.e., mutations) or outside (i.e., changes in hormonal balance) that result in derangements of the prostate gland. Finally, environmental and genetic factors that lead to prostate carcinogenesis including activation of oncogenes and mutations of tumor suppressor genes are also discussed.

Animals↗
PubMed2000

MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis.

The matrix metalloproteinase MMP-9/gelatinase B is upregulated in angiogenic dysplasias and invasive cancers of the epidermis in a mouse model of multi-stage tumorigenesis elicited by HPV16 oncogenes. Transgenic mice lacking MMP-9 show reduced keratinocyte hyperproliferation at all neoplastic stages and a decreased incidence of invasive tumors. Yet those carcinomas that do arise in the absence of MMP-9 exhibit a greater loss of keratinocyte differentiation, indicative of a more aggressive and higher grade tumor. Notably, MMP-9 is predominantly expressed in neutrophils, macrophages, and mast cells, rather than in oncogene-positive neoplastic cells. Chimeric mice expressing MMP-9 only in cells of hematopoietic origin, produced by bone marrow transplantation, reconstitute the MMP-9-dependent contributions to squamous carcinogenesis. Thus, inflammatory cells can be coconspirators in carcinogenesis.

Animals↗
PubMed1998

Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.

Oct4 is a mammalian POU transcription factor expressed by early embryo cells and germ cells. We report that the activity of Oct4 is essential for the identity of the pluripotential founder cell population in the mammalian embryo. Oct4-deficient embryos develop to the blastocyst stage, but the inner cell mass cells are not pluripotent. Instead, they are restricted to differentiation along the extraembryonic trophoblast lineage. Furthermore, in the absence of a true inner cell mass, trophoblast proliferation is not maintained in Oct4-/- embryos. Expansion of trophoblast precursors is restored, however, by an Oct4 target gene product, fibroblast growth factor-4. Therefore, Oct4 also determines paracrine growth factor signaling from stem cells to the trophectoderm.

Animals↗
PubMed2001

Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila.

The JAK/STAT signaling pathway, renowned for its effects on cell proliferation and survival, is constitutively active in various human cancers, including ovarian. We have found that JAK and STAT are required to convert the border cells in the Drosophila ovary from stationary, epithelial cells to migratory, invasive cells. The ligand for this pathway, Unpaired (UPD), is expressed by two central cells within the migratory cell cluster. Mutations in upd or jak cause defects in migration and a reduction in the number of cells recruited to the cluster. Ectopic expression of either UPD or JAK is sufficient to induce extra epithelial cells to migrate. Thus, a localized signal activates the JAK/STAT pathway in neighboring epithelial cells, causing them to become invasive.

Animals↗
PubMed2001

Expression of vascular endothelial growth factor and its receptors in multiple myeloma and other hematopoietic malignancies.

Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with biologic effects that include regulation of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine generation. The importance of angiogenic factors such as VEGF, while clearly established in solid tumors, has not been fully elucidated in human hematopoietic neoplasms. Human hematopoietic tumor cell lines, representing multiple lineages and diseases, produce and secrete VEGF and express at least one of its two receptors. Exposure of human vascular endothelial cells to VEGF increased the expression of several hematopoietic growth factors known to be involved in myeloma including interleukin-6 (IL-6). Bone marrow samples from patients diagnosed with multiple myeloma were examined for expression of VEGF and its receptors. VEGF protein production was detected in malignant plasma cells from 78% of the myeloma patients studied. While expression of the Flt-1 and KDR receptors was not observed in the malignant plasma cells, both were markedly elevated in the normal marrow myeloid and monocytic cells surrounding the tumor. In bone marrow clot sections from normal allogeneic donors, low-intensity cytoplasmic VEGF expression was detected infrequently in isolated myelocytes, macrophages, and megakaryocytes. In vitro colony-forming assays using patient-derived material revealed that antibody neutralization of VEGF resulted in an inhibition of colony growth, whereas the addition of recombinant human VEGF stimulated colony formation. Neutralization of VEGF activity also suppressed the generation of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) from bone marrow mononuclear cells. These data raise the possibility that VEGF may play a role in the growth of hematopoietic neoplasms such as multiple myeloma through paracrine and perhaps autocrine mechanisms.

Bone Marrow Cells↗
PubMed1999

Paracrine neurotransmission in the CNS: involvement of 5-HT.

While GABA and glutamate have an established synaptic function in the CNS, recent evidence suggests 5-HT neurotransmission is predominantly paracrine. As the amino-acid neurotransmitters interact with receptors that produce effects rapidly, electrophysiological approaches can be used to assess the time delay between transmitter release and the postsynaptic response directly. However, this approach cannot be used for studies of 5-HT-mediated neurotransmission, because the majority of its receptors react more slowly, so anatomical and voltammetrical approaches have been used to provide insight into 5-HT-mediated events. These studies have revealed that extrasynaptic receptors and transporters for 5-HT exist, and that 5-HT escapes readily from the synaptic cleft. Attenuation of 5-HT binding by 5-HT-receptor antagonists and 5-HT-uptake inhibitors does not affect the synaptic efflux elicited by transient stimuli, although the effects of such drugs are apparent at later time points. Once it is extrasynaptic, 5-HT has a concentration that is similar to those estimated to be optimal for receptor and transporter activation, and it can diffuse a few micrometers until removed by its transporter. These properties of 5-HT raise the possibility that it can act on receptors that are distant from its release site and function as a paracrine transmitter.

Central Nervous System↗
PubMed2003

Reciprocal paracrine pathways link atrial natriuretic peptide and somatostatin secretion in the antrum of the stomach.

Atrial natriuretic peptide (ANP) as well as its receptor, NPR-A, have been identified in gastric antral mucosa, suggesting that ANP may act in a paracrine fashion to regulate gastric secretion. In the present study, we have superfused antral mucosal segments obtained from rat stomach to examine the paracrine pathways linking ANP and somatostatin secretion in this region.ANP (0.1 pM to 0.1 microM) caused a concentration-dependent increase in somatostatin secretion (EC(50), 0.3 nM). The somatostatin response to ANP was unaffected by the axonal blocker tetrodotoxin but abolished by addition of the selective NPR-A antagonist, anantin. Anantin alone inhibited somatostatin secretion by 18+/-3% (P<0.005), implying that endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion. Somatostatin (1 pM to 1 microM) caused a concentration-dependent decrease in ANP secretion (EC(50), 0.7 nM) that was abolished by addition of the somatostatin subtype 2 receptor (sst2) antagonist, PRL2903. Neutralization of ambient somatostatin with somatostatin antibody (final dilution 1:200) increased basal ANP secretion by 70+/-8% (P<001), implying that endogenous somatostatin inhibits ANP secretion. We conclude that antral ANP and somatostatin secretion are linked by paracrine feedback pathways: endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion, and endogenous somatostatin, acting via the sst2 receptor, inhibits ANP secretion.

Animals↗
PubMed2003

Paracrine effects of PAMP and adrenomedullin on the human adrenal H295R cell line: PAMP but not adrenomedullin stimulates DHEA secretion.

It has previously been shown, by this laboratory and others, that adrenal cells actively secrete adrenomedullin. Here it is demonstrated that human adrenal cells also secrete the related peptide, proadrenomedullin N-terminal 20 peptide (PAMP). The actions of adrenomedullin and PAMP on adrenal steroid secretion were determined by measuring the aldosterone, cortisol and dehydroepiandrosterone (DHEA) content of cell culture medium after exposure of the human adrenal H295R cells to either PAMP or adrenomedullin. While PAMP was found to cause a dose-dependent increase in release of all the steroids into the medium, adrenomedullin only increased aldosterone and cortisol and had no effect on DHEA. These data suggest that both adrenomedullin and PAMP may be autocrine regulators of adrenal steroid secretion.

Adrenal Cortex↗
PubMed2002

Overexpression of chemokine-like factor 2 promotes the proliferation and survival of C2C12 skeletal muscle cells.

Chemokine-like factor 1 (CKLF1) is a novel cytokine first cloned from U937 cells. It contains different splicing forms and has chemotactic effects on a wide spectrum of cells both in vitro and in vivo; it can also stimulate the regeneration of skeletal muscle cells in vivo, but the mechanism remains unclear. To probe the myogenesis function of CKLF2, which is the largest isoform of CKLFs, C2C12 murine myoblasts were stably transfected with human CKLF2 eukaryotic expression vector. Compared with control vector transfected C2C12 cells, CKLF2 overexpression causes accelerated myoblast proliferation as determined by cell counting and [(3)H]TdR incorporation assays. In addition, CKLF2 overexpression also promotes cell differentiation, which was determined by higher expression levels of myogenin, creatine kinase, myosin and the accelerated myoblast fusion. Further analysis also indicates that CKLF2 could activate the transcription activity of the bHLH/MyoD and MEF2 families. Finally, DNA synthesis and myotube formation could also be promoted by growing C2C12 cells in conditioned media from CKLF2-transfected cells. These findings strongly suggest a role for human CKLF2 in regulation of skeletal muscle myogenesis.

Animals↗
PubMed2000

Epidermal growth factor is decreased in liver of rats with biliary cirrhosis but does not act as paracrine growth factor immediately after hepatectomy.

BACKGROUND/AIMS: Epidermal growth factor, a potent mitogen for hepatocytes and cholangiocytes, is thought to act as an immediate-early gene after partial hepatectomy. Since regeneration is impaired in cirrhosis, we explored the expression of epidermal growth factor in cirrhotic rat liver immediately after partial hepatectomy. METHODS: Cirrhosis was induced by bile duct ligation (n=21); sham-operated animals served as controls (n=21). Twenty-five days after initial surgery animals were subjected to 70% partial hepatectomy or sham operation; the liver was sampled before surgery and 20, 40 and 90 min thereafter. Epidermal growth factor mRNA levels were assessed by quantitative reverse transcription polymerase chain reaction. Protein expression was estimated by immunohistochemistry using a polyclonal antibody against epidermal growth factor. RESULTS: Before hepatectomy, epidermal growth factor mRNA averaged 70.3+/-39.9 pg/microg of total RNA in controls; this was markedly decreased to 21.9+/-12.7 pg/microg RNA in bile duct ligation (p<0.01). Epidermal growth factor mRNA did not increase after partial hepatectomy in either group, with the exception of sham-operated controls. Immunohistochemistry revealed that partial hepatectomy had no effect on epidermal growth factor expression. Hepatocytes showed uniformly cytosolic epidermal growth factor in controls, while in bile duct ligation immunostaining was faint or absent. Cholangiocytes exhibited a strong cytosolic staining in all experimental groups. CONCLUSIONS: The present study shows that epidermal growth factor is reduced in the cirrhotic liver. This could contribute to the loss of parenchymal liver tissue observed in cirrhosis. The lack of up-regulation after PH sheds doubt on the role of epidermal growth factor as an immediate-early gene in hepatic regeneration. Further, we demonstrate that epidermal growth factor accumulates in cholangiocytes. This observation is strong evidence for involvement of the mitogen epidermal growth factor in the proliferation of bile ducts during cirrhogenesis.

Animals↗
PubMed1998

Expression of different isoforms of TGF-beta and the latent TGF-beta binding protein (LTBP) by rat Kupffer cells.

BACKGROUND/AIMS: Kupffer cells (liver resident macrophages) make an important contribution to the perpetuation of liver diseases by synthesis and secretion of TGF-beta. In some cell types TGF-beta, is expressed as a large latent complex containing the latent TGF-beta binding protein (LTBP) in addition to the N-terminal TGF-beta precursor (latency associated peptide). This study aimed to identify LTBP expression in rat Kupffer cells. METHODS: Cells were isolated from rat liver by collagenase-pronase reperfusion, purified and cultured under standard conditions. TGF-beta and LTBP expression were characterized using alkaline phosphatase-anti-alkaline phosphatase immunostainings, reverse transcription-polymerase chain reaction and immunoprecipitation of metabolically labeled proteins. RESULTS: Immunostainings of Kupffer cells with anti-sera against LTBP-1 (ab 39) and LTBP-2 indicated the expression of both LTBP isoforms in addition to the expression of latency associated peptide and TGF-beta. Transcripts of three LTBP isoforms (LTBP-1,-2,-3) and TGF-beta isoforms (TGF-beta-1,-2,-3) were detectable by reverse transcription-polymerase chain reaction. The LTBP-1D splice variant missing a part of the proteinase sensitive hinge region which has recently been described in hepatic stellate cells is expressed in Kupffer cells, too. Metabolic labeling of Kupffer cells with [35S]-Met/Cys followed by immunoprecipitation of the conditioned media using antisera against LTBP-1 and LTBP-2 indicated the secretion of high molecular mass TGF-beta complexes containing LTBP proteins of 230 and 170 kDa (LTBP-1) or 230 kDa (LTBP-2). CONCLUSION: The results show that Kupffer cells partly synthesize and release TGF-beta as large latent complexes. This requires the extracellular activation of TGF-beta as a prerequisite for receptor binding and cellular signaling.

Animals↗
PubMed1999

Paracrine or virus-mediated induction of decorin expression by endothelial cells contributes to tube formation and prevention of apoptosis in collagen lattices.

Resting endothelial cells express the small proteoglycan biglycan, whereas sprouting endothelial cells also synthesize decorin, a related proteoglycan. Here we show that decorin is expressed in endothelial cells in human granulomatous tissue. For in vitro investigations, the human endothelium-derived cell line, EA.hy 926, was cultured for 6 or more days in the presence of 1% fetal calf serum on top of or within floating collagen lattices which were also populated by a small number of rat fibroblasts. Endothelial cells aligned in cord-like structures and developed cavities that were surrounded by human decorin. About 14% and 20% of endothelial cells became apoptotic after 6 and 12 days of co-culture, respectively. In the absence of fibroblasts, however, the extent of apoptosis was about 60% after 12 days, and cord-like structures were not formed nor could decorin production be induced. This was also the case when lattices populated by EA.hy 926 cells were maintained under one of the following conditions: 1) 10% fetal calf serum; 2) fibroblast-conditioned media; 3) exogenous decorin; or 4) treatment with individual growth factors known to be involved in angiogenesis. The mechanism(s) by which fibroblasts induce an angiogenic phenotype in EA.hy 926 cells is (are) not known, but a causal relationship between decorin expression and endothelial cell phenotype was suggested by transducing human decorin cDNA into EA.hy 926 cells using a replication-deficient adenovirus. When the transduced cells were cultured in collagen lattices, there was no requirement of fibroblasts for the formation of capillary-like structures and apoptosis was reduced. Thus, decorin expression seems to be of special importance for the survival of EA.hy 926 cells as well as for cord and tube formation in this angiogenesis model.

Adenoviridae↗
PubMedDate not supplied

Neuroendocrine vs. paracrine control of follicle-stimulating hormone.

In spite of the pivotal role FSH plays in the regulation of gametogenesis, we are far from understanding the regulatory mechanisms involved in the control of its synthesis, secretion, and functions. Part of the problem relates to its molecular heterogeneity and the unavailability of assay methods capable of distinguishing the various isoforms of FSH. Recent work has confirmed the existence of two modes of FSH secretion, the basal and the episodic modes. The major portion of FSH secretion appears to be in the basal mode. The episodic mode appears to consist of both GnRH-associated and non-GnRH-associated pulses of FSH. The intracellular mechanisms by which differential release of LH and FSH are facilitated by GnRH are just beginning to be unraveled and may involve different second-messenger systems. Local pituitary regulators such as activins, inhibins, and follistatins are receiving considerable attention in recent years as a means by which differential release of LH and FSH can be facilitated by GnRH and other neuroendocrine factors. In parallel, the search for a selective FSH-releasing factor (FSH-RF) continues. Identification of variant forms of GnRH in recent years has opened up the possibility that one GnRH variant may be the long-sought-after FSH-RF. From a functional aspect, an understanding of how FSH heterogeneity is regulated is also important, as the different mixes of FSH isoforms have the ability to fine-tune the follicular recruitment and selection process. This review focuses on the recent advances made in the neuroendocrine and paracrine regulation of FSH synthesis/secretion/heterogeneity and pinpoints areas of gaps in our knowledge.

Activins↗