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At least 91 records · Page 5Linked to original sources
PubMed2004

High local concentrations and effects on differentiation implicate interleukin-6 as a paracrine regulator.

OBJECTIVE: To examine the possibility that interleukin-6 (IL-6) can act as a paracrine regulator in adipose tissue by examining effects on adipogenic genes and measuring interstitial IL-6 concentrations in situ. RESEARCH METHODS AND PROCEDURES: Circulating and interstitial IL-6 concentrations in abdominal and femoral adipose tissue were measured using the calibrated microdialysis technique in 20 healthy male subjects. The effects of adipose cell enlargement on gene expression and IL-6 secretion were examined, as well as the effect of IL-6 in vitro on gene expression of adiponectin and other markers of adipocyte differentiation. RESULTS: The IL-6 concentration in the interstitial fluid was approximately 100-fold higher than that in plasma, suggesting that IL-6 may be a paracrine regulator of adipose tissue. This was further supported by the finding that adding IL-6 in vitro at similar concentrations down-regulated the expression of adiponectin, aP2, and PPARgamma-2 in cultured human adipose tissue. In addition, gene expression and release of IL-6, both in vivo and in vitro, correlated with adipose cell size. DISCUSSION: These data suggest that IL-6 may be a paracrine regulator of adipose tissue. Furthermore, increased adipose tissue production of IL-6 after hypertrophic enlargement of the adipose cells may detrimentally affect systemic insulin action by inducing adipose tissue dysfunction with impaired differentiation of the pre-adipocytes and/or adipocytes and lower adiponectin.

Abdomen↗
PubMed1997

Inhibition of paracrine angiotensin-converting enzyme in vivo: effects on interstitial glucose and lactate concentrations in human skeletal muscle.

Microdialysis was used to selectively assess the effect of the paracrine renin-angiotensin system (RAS) on interstitial glucose and lactate concentration profiles in skeletal muscle of healthy volunteers (n = 8) during basal and insulin-stimulated conditions. Paracrine RAS was selectively inhibited by local retrodialysis with enalaprilate. Under basal conditions, local administration of enalaprilate (2 micrograms mL-1) increased interstitial dialysate glucose concentration from 0.71 +/- 0.14 mmol L-1 to 0.84 +/- 0.14 mmol L-1 and decreased the serum interstitial gradient (SIGglu) compared with baseline (P < 0.02). Under clamp conditions, enalaprilate, even at the lowest concentration (0.02 microgram mL-1), increased interstitial dialysate glucose concentration from 0.77 +/- 0.11 mmol L-1 to 1.02 +/- 0.09 mmol L-1 and decreased SIGglu compared with baseline (P < 0.01). Interstitial lactate concentrations slightly increased during basal as well as during clamp conditions (P < 0.05 vs. baseline). Selective inhibition of paracrine muscle angiotensin-converting enzyme (ACE) increases interstitial glucose and lactate concentrations and decreases SIGglu in muscle by facilitating transcapillary glucose transport. This effect is more pronounced during hyperinsulinaemia and may be of clinical relevance in diabetic patients treated with therapeutic doses of enalapril.

Adult↗
PubMed1999

Alpha2-macroglobulin reduces paracrine- and autocrine-stimulated matrix synthesis of cultured rat hepatic stellate cells.

BACKGROUND: Transforming growth factor beta1 (TGF-beta1) is considered to represent a major fibrogenic mediator in the liver. The aim of the present study was to investigate whether alpha2-macroglobulin (alpha2M) might reduce paracrine- and autocrine-stimulated matrix synthesis of cultured rat hepatic stellate cells (HSCs) by scavenging TGF-beta. METHODS AND RESULTS: Using native agarose electrophoresis, we demonstrated that alpha2M binds [125I]-TGF-beta1 within minutes. Preincubation of transiently acidified supernatants of cultured Kupffer cells, secondary cultured (activated) HSC and platelet lysate with, respectively, 500 and 2000 microg mL-1 alpha2M significantly reduced the concentration of active TGF-beta1 in these media. As a consequence of TGF-beta scavenging by alpha2M, paracrine-stimulated proteoglycan synthesis of primary cultured HSCs was reduced significantly. Furthermore, addition of 200 microg mL-1 alpha2M to passaged (activated) HSCs resulted in (a) a reduction in autocrine-stimulated extracellular matrix synthesis (proteoglycan -52%, fibronectin -55%) and (b) increased cell proliferation. A similar reduction in matrix synthesis was observed after the addition of 5 micromol L-1 TGF-beta1 antisense oligonucleotide to activated HSCs. CONCLUSION: We conclude that alpha2M reduces paracrine-and autocrine-stimulated extracellular matrix synthesis of cultured HSCs by scavenging TGF-beta. These mechanisms might restrict liver fibrogenesis.

Animals↗
PubMedDate not supplied

Paracrine changes in the peritoneal environment of women with endometriosis.

During the past decade, macrophage-derived substances such as prostanoids, cytokines, growth factors and angiogenic factors have been detected in the peritoneal fluid of women with endometriosis. In particular, growth-promoting and angiogenic factors are considered to be substantially involved in the pathogenesis of endometriosis. In this study, vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta) and intercellular adhesion molecule 1 (ICAM-1), substances recently detected in the peritoneal fluid of women with endometriosis, were assessed with regard to their concentrations in different stages of endometriosis and changes of the peritoneal paracrine activity after medical treatment with a gonadotrophin releasing hormone agonist (GnRHa). Peritoneal fluid was obtained from patients with endometriosis during laparoscopy before and after a 4-month treatment with a GnRHa. VEGF, TGF-beta and ICAM-1 could be detected in all women presenting with various stages of active endometriosis. After GnRHa therapy, all patients showed significant decreases in mean concentrations of VEGF (194+/-77 pg/ml), TGF-beta (902+/-273 pg/ml) and ICAM-1 (157+/-52 ng/ml). Patients with stage III and IV endometriosis (according to the rAFS score) had much higher concentrations of VEGF and TGF-beta before treatment compared with those patients with mild endometriosis (rAFS stages I and II). The most striking decrease in concentration was for TGF-beta, from 902 pg/ml before to 273 pg/ml after therapy. These results indicate an important role for paracrine activity in the establishment and maintenance of endometriosis. Indeed, treatment with a GnRHa may reduce paracrine activity in the peritoneal cavity via hypo-oestrogenism and provide proof of successful therapy.

Ascitic Fluid↗
PubMed1996

Systemic and local paracrine cytokine therapies using transduced tumor cells are synergistic in treating intracranial tumors.

Development of an effective immunotherapeutic approach for treatment of CNS tumors must take into account the unique anatomic and immunologic features of the brain. We explored the antitumor immune response in the brain elicited by nonreplicating melanoma cells genetically engineered to produce either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) in a paracrine fashion. Using a new model of intracranial melanoma in C57BL/6 mice, the cytokine-producing cells were given either as a subcutaneous vaccine to induce systemic antitumor immunity or as a direct injection into the brain as local immunotherapy. We found that GM-CSF-transduced cells, as a subcutaneous vaccine but not as an intracranial injection, afforded some protection from intracranial challenge with the wild-type tumor. In contrast, direct intracranial injection of tumor cells secreting IL-2 was protective whereas flank vaccination with IL-2 transductants was not. Combination therapy with both the subcutaneous GM-CSF-transductants as a vaccine and local administration of IL-2-transductants in the brain achieved a synergistic response. These findings provide a basis for the application of paracrine cytokine delivery to brain cancer therapy both as a systemic vaccine and via local administration. The demonstration of synergy between paracrine cytokine therapies holds promise as a novel therapy for brain tumors.

Animals↗
PubMed1987

Paracrine regulation of gastric acid secretion by fundic somatostatin.

The isolated, luminally perfused mouse stomach was used to determine whether somatostatin cells located in proximity to parietal cells exert a paracrine influence on acid secretion. Acid secretion in response to histamine and pentagastrin was accompanied by a dose-dependent increase in somatostatin secretion. Incubation of the stomach with somatostatin antiserum (final dilution 1:100), but not with normal serum, augmented significantly basal and secretagogue-stimulated acid secretion. The augmentation was most evident with submaximal stimuli (92 +/- 18%, P less than 0.01, with 15 microM pentagastrin and 160 +/- 6%, P less than 0.001, with 5 microM histamine) and least evident with maximal stimuli (30 +/- 12%, P less than 0.05, with 200 microM histamine). The acid response to submaximal field stimulation (10 V, 20 Hz, 0.5 ms), which was accompanied by an increase in somatostatin secretion, was also augmented by somatostatin antiserum (115 +/- 12%, P less than 0.01), whereas the response to maximal field stimulation (20 V, 20 Hz, 0.5 ms), which was accompanied by a decrease in somatostatin secretion, a typically cholinergic effect, was not augmented further. It is concluded that fundic somatostatin modulates the acid secretory response to paracrine (histamine), hormonal (gastrin), and neural (acetylcholine) stimuli and that cholinergic stimulation of acid secretion reflects both the direct effect of acetylcholine on the parietal cell and its ability to eliminate the paracrine restraint exerted by somatostatin.

Animals↗
PubMed1997

Reciprocal inhibitory paracrine pathways link histamine and somatostatin secretion in the fundus of the stomach.

The present study was designed to examine the functional linkage between histamine and somatostatin secretion in the fundus of the stomach. In segments of rat fundic mucosa, superfusion with thioperamide (H3 antagonist) increased somatostatin and decreased histamine secretion; superfusion with (R)(-)-alpha-methylhistamine (H3 agonist) had the opposite effect, decreasing somatostatin and increasing histamine secretion. The pattern implied that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on somatostatin secretion. Superfusion with somatostatin antibody (1:250) increased histamine secretion, implying that endogenous somatostatin, in turn, exerts an inhibitory paracrine influence on histamine secretion. Somatostatin antibody also abolished the decrease in histamine secretion induced by thioperamide and the increase in histamine secretion induced by (R)(-)-alpha-methylhistamine, implying that changes in histamine secretion induced by activation of H3 receptors reflect changes in somatostatin secretion. Superfusion with the muscarinic agonist methacholine alone and in the presence of either H3 agonist or H3 antagonist confirmed the existence of reciprocal inhibitory pathways linking somatostatin and histamine. We conclude that fundic histamine and somatostatin secretion are linked via reciprocal inhibitory paracrine pathways that serve to amplify the regulatory influence of somatostatin.

Animals↗
PubMed1999

Autocrine and paracrine actions of intestinal fibroblast-derived insulin-like growth factors.

Paracrine and autocrine actions of the insulin-like growth factors (IGFs) are inferred by local expression within the bowel. CCD-18Co cells, IEC-6 cells, and immunoneutralization were used to analyze whether IGFs have direct autocrine or paracrine effects on proliferation of cultured intestinal fibroblasts and epithelial cells. Growth factor expression was analyzed by ribonuclease protection assay and RT-PCR. Extracellular matrix (ECM) was analyzed for effects on cell proliferation. CCD-18Co cells express IGF-II mRNAs and low levels of IGF-I mRNA. Conditioned medium from CCD-18Co cells (CCD-CM) stimulated proliferation of IEC-6 and CCD-18Co cells. Neutralization of IGF immunoreactivity in CCD-CM reduced but did not abolish this effect. RT-PCR and immunoneutralization demonstrated that other growth factors contribute to mitogenic activity of CCD-CM. Preincubation of CCD-CM with ECM prepared from IEC-6 or CCD-18Co cells reduced its mitogenic activity. ECM from CCD-18Co cells enhanced growth factor-dependent proliferation of IEC-6 cells. IEC-6 cell ECM inhibited IGF-I action on CCD-18Co cells. We conclude that IGF-II is a potent autocrine mitogen for intestinal fibroblasts. IGF-II interacts with other fibroblast-derived growth factors and ECM to stimulate proliferation of intestinal epithelial cells in a paracrine manner.

Animals↗
PubMed1998

Integrating multiple paracrine regulators of renal microvascular dynamics.

There has been tremendous growth in our knowledge about the multiple interacting mechanisms that regulate renal microvascular function. Paracrine signals originating from endothelial and epithelial cells exert profound influences on the basal tone and reactivity of the pre- and postglomerular arterioles. Selective responsiveness of these arterioles to various stimuli is possible because of differential activating mechanisms in vascular smooth muscle cells of afferent and efferent arterioles. Afferent arterioles rely predominantly on voltage-dependent calcium channels, while efferent arterioles utilize other mechanisms for calcium entry as well as intracellular calcium mobilization. The autoregulatory responses of preglomerular arterioles exemplify the selectivity of these complex control mechanisms. The myogenic mechanism responds to increases in renal perfusion pressure through "stretch-activated" cation channels that lead to depolarization, calcium entry, and vascular contraction. Autoregulatory efficiency is enhanced by the tubuloglomerular feedback (TGF) mechanism which responds to flow-dependent changes in tubular fluid composition at the level of the macula densa and transmits signals to the afferent arterioles to alter the activation state of voltage-dependent calcium channels. Recent studies have implicated extracellular ATP as one paracrine factor mediating TGF and autoregulatory related signals to the afferent arterioles. Other paracrine agents including nitric oxide, angiotensin II, adenosine, and arachidonic acid metabolites modulate vascular responsiveness in order to maintain an optimal balance between the metabolically determined reabsorptive capabilities of the tubules and the hemodynamically dependent filtered load.

Animals↗
PubMed1989

Regulation of Sertoli cell function and differentiation through the actions of a testicular paracrine factor P-Mod-S.

The current study was designed to investigate the actions of the testicular paracrine factor P-Mod-S on Sertoli cell function and differentiation. Transferrin production by Sertoli cells was stimulated by P-Mod-S to a greater extent than any individual regulatory agent and in a manner similar to a combination of FSH, insulin, retinol, and testosterone (FIRT). P-Mod-S had an additive response in combination with FIRT. The increase in transferrin production with a combination of P-Mod-S and FIRT is the highest level of stimulation (up to 8-fold) observed. These profound effects of P-Mod-S on Sertoli cell function implied a potential unique mechanism of action for the paracrine factor. FSH and FIRT significantly stimulated cAMP levels with both 60-min and 72-h treatments. In contrast, P-Mod-S had no effect on cAMP levels with a 60-min treatment and only a small increase with a 72-h treatment. Interestingly, P-Mod-S stimulated cGMP levels that remained above basal levels up to 72 h of treatment. FSH had no effect on cGMP levels. P-Mod-S did not affect inositol phosphate hydrolysis with treatments between 15 and 60 min. The actions of P-Mod-S on cGMP levels influenced Sertoli cell function on a molecular level. Northern blot analysis indicated that P-Mod-S and FIRT both stimulated the apparent levels of the 2.6-kilobase transcript of transferrin and the 1.7-kilobase transcript of androgen-binding protein. A solution hybridization procedure was used to quantitate the influence of P-Mod-S on Sertoli cell gene expression. P-Mod-S stimulated steady state levels of both transferrin and androgen-binding protein message approximately 2-fold, similar to the effects of FIRT. Both forms of P-Mod-S had similar biological activities and mechanisms of action. P-Mod-S (A) and P-Mod-S (B) both stimulated cGMP, altered Sertoli cell gene expression, and had profound effects on transferrin production. Although slightly different biochemically, both forms of P-Mod-S appear to be functionally similar. Combined observations indicate that the paracrine factor produced by peritubular cells, P-Mod-S, acts on Sertoli cells in part through a cGMP-mediated response to influence the expression of specific genes which subsequently have profound effects on Sertoli cell function and differentiation.

Androgen-Binding Protein↗
PubMed2001

Production and metabolism of serotonin (5-HT) by the human adrenal cortex: paracrine stimulation of aldosterone secretion by 5-HT.

In the human adrenal cortex, serotonin (5-HT) is contained in mast-like cells, and we have shown that 5-HT stimulates aldosterone secretion, suggesting that 5-HT may control glomerulosa cells through a paracrine mechanism. Concurrently, the presence of 5-hydroxyindolacetic acid in human adrenocortical extracts indicates that 5-HT may be metabolized after local release by mast cells. The aim of the present study was to investigate in vitro the production and metabolism of 5-HT by the human adrenal cortex. Perifused adrenal slices released spontaneously detectable amounts of 5-HT (0.74 +/- 0.38 fmol/mg wet tissue.min). The mast cell-depleting drug compound 48/80 induced a burst of 5-HT secretion followed by a gradual increase in aldosterone production. Administration of the specific 5-HT(4) receptor antagonist GR 113808 (10(-6) M) did not affect compound 48/80-induced 5-HT release but abolished the stimulatory effect of compound 48/80 on aldosterone secretion, indicating that 5-HT released locally is responsible for a paracrine control of steroidogenesis. Incubation of cells from the human adrenal cortex with 5-HT (10(-5) M) provoked the formation of the 5-HT metabolite 5-hydroxytryptophol. The type A monoamine oxidase (MAO) inhibitor clorgyline (10(-6) M) suppressed the metabolism of 5-HT into 5-hydroxytryptophol. Immunocytochemical staining of cultured cells revealed the presence of a subpopulation of MAO-A-positive cells. Double labeling with an antiserum against chromogranin A showed that MAO-A was actually contained in chromaffin cells. Similarly, immunohistochemical staining of adrenal slices showed that MAO-A was expressed in chromaffin cells located both in the medulla and in intracortical rays. In conclusion, the present study shows that, in the human adrenal cortex, 5-HT, released by mast-cells, may stimulate aldosterone secretion in a paracrine manner. Our data also indicate that 5-HT is metabolized by MAO-A located in intracortical chromaffin cells.

Adrenal Cortex↗
PubMed2000

A role of pituitary adenylate cyclase activating polypeptide (PACAP) as a regulator of paracrine interactions between folliculo-stellate cells and gonadotropes through the control of activin-follistatin interactions.

Pituitary folliculo-stellate (FS) cells were able to modify the effect of activin-A on gonadotropes through the paracrine factor, follistatin. The present study was aimed to examine whether a hypothalamic peptide, pituitary adenylate cyclase activating polypeptide (PACAP), could be a regulator of this paracrine interaction. Co-culture of FS cell-originated cell line TtT/GF cells with rat anterior pituitary cells showed faint inhibitory effect on the stimulatory action of activin-A on FSH secretion. When PACAP was added to the culture during the co-culture period, however, the presence of TtT/GF cells caused significant suppression of the effect of activin-A on FSH secretion. Conditioned-media (CM) from TtT/GF cells, obtained by incubation of TtT/GF cells in the presence or absence of PACAP, were next added to the cultures of anterior pituitary cells alone. CM from TtT/GF cells without PACAP treatment revealed slight, but not significant, suppressive effect on activin-induced increases in FSH secretion and the percentage of FSH cells. Meanwhile, CM from PACAP-treated TtT/GF cells attenuated both effects of activin-A. Furthermore, the inhibitory effect of the CM was neutralized when follistatin antibody was present in the culture. These results suggest that PACAP is able to regulate the paracrine action of FS cells on pituitary gonadotropes. Besides expressing direct actions on pituitary endocrine cells, PACAP may have roles as a regulator of cell-to-cell interactions within the pituitary gland.

Activins↗
PubMed1994

Differences in binding to the solid substratum and extracellular matrix may explain isoform-specific paracrine effects of platelet-derived growth factor.

We have studied the paracrine response of fibroblasts to the two homodimeric isoforms of platelet-derived growth factor (PDGF-AA and -BB). CHO-cells stably transfected with a B-chain cDNA expression vector (CHO-PDGF-B cells), were found to elicit a marked paracrine response when seeded at clonal density on preformed monolayers of human or murine fibroblasts; no such response was elicited by CHO-PDGF-A cells. Immunofluorescence microscopy of CHO-PDGF-B cell cultures showed the presence of a pericellular deposit of material reacting with antibodies against PDGF-BB; no corresponding PDGF-AA immunoreactive material was found in the CHO-PDGF-A cultures. The pericellular material, deposited by CHO-PDGF-B cells, was shown to have a growth promoting effect on target cells. Furthermore, we could show that 125I-PDGF-BB binds more efficiently than 125I-PDGF-AA to extracellular matrix prepared from foreskin fibroblast cultures, as well as to defined extracellular matrix components (fibronectin, laminin and collagen III). The results reveal a marked difference in the paracrine activity of PDGF-AA and PDGF-BB; the latter has a strong local growth enhancing effect, that is mostly likely to be ascribed to its association with components of the extracellular matrix.

3T3 Cells↗
PubMed2001

Conversion from a paracrine to an autocrine mechanism of androgen-stimulated growth during malignant transformation of prostatic epithelial cells.

Normal adult prostate epithelium of both human and rat origin was transplanted with Matrigel into intact or androgen-ablated (i.e., castrated) nude mice. Within these transplants, an influx of mouse mesenchymal cells was one of the earliest events to occur resulting in the development of a collar of smooth muscle cells and fibroblasts surrounding the transplanted epithelium. A subset of these surrounding stromal cells express androgen receptor (AR). The surrounded transplanted epithelium initially expresses high molecular weight cytokeratins characteristic of prostatic basal cells and AR. In both intact and androgen-ablated hosts, this epithelium subsequently develops a patent lumen producing a rudimentary glandular acini. Only in the nonablated hosts, however, do these rudimentary acini undergo a further proliferative growth phase, as determined by Ki67 immunocytochemical stainings and the development of a low molecular weight cytokeratin positive layer of luminal (i.e., secretory) epithelial cells. Because AR is expressed in both the donor epithelium and host (i.e., mouse) stromal cells, this androgen-stimulated growth response could involve either autocrine pathways initiated within donor normal adult epithelial cells themselves or paracrine pathways initiated within the AR-expressing subset of mouse stromal cells. To resolve this issue, mice carrying the testicular feminized mutation in the X-linked AR gene were cross-bred to AR-wt nude mice to produce AR-null nude male mice. None of the cells in these AR-null nude male mice express functional AR protein. Therefore, these animals can be used to prevent any possibility of host stromal cell paracrine involvement in initiating an androgen-stimulated growth response when normal adult or malignant prostatic epithelial cells are transplanted into these null hosts. In these AR-null nude male mice, the androgen-stimulated growth of normal adult prostatic epithelial cells did not occur (i.e., androgen-induced growth response of normal prostatic epithelial cells requires stromal cell paracrine involvement). In contrast, using four different prostatic cancer models (i.e., human PC-82, human LNCaP, human LAPC-4, and rat R3327G), the androgen-stimulated growth of prostatic cancer cells occurred identically in both AR-null and AR-wt nude male mice (i.e., a direct autocrine mechanism is responsible for androgen-stimulated growth of malignant prostatic epithelial cells). In summary, a fundamental change in the mechanism for androgen-stimulated growth occurs during the transformation from normal to malignant prostatic epithelial cells.

Androgens↗
PubMedDate not supplied

Role of nerve growth factor-like protein in the paracrine regulation of prostate growth.

Prostate cancer is the most commonly diagnosed form of malignant neoplasia in men. Considerable evidence has accumulated suggesting that paracrine interactions between stromal cells and epithelial cells mediate, in part, the growth and development of the prostate. A nerve growth factor-like protein secreted by stromal cells has been implicated in the paracrine regulation of prostate epithelial tumor cell growth in vitro. This prostate-derived nerve growth factor-like protein differs from the known members of the neurotrophin family of proteins, and may represent a prostate-specific form of this family of gene products. Furthermore, corresponding nerve growth factor receptors have been localized to the epithelial cells of the human prostate in vivo, consistent with a role of the receptors and the adjacent nerve growth factor-like protein secreted by stromal cells, in the paracrine regulation of prostate growth and neoplasia.

Humans↗
PubMedDate not supplied

Neural, hormonal, and paracrine regulation of gastrin and acid secretion.

Physiological stimuli from inside and outside the stomach coverage on gastric effector neurons that are the primary regulators of acid secretion. The effector neurons comprise cholinergic neurons and two types of non-cholinergic neurons: bombesin/GRP and VIP neurons. The neurons act directly on target cells or indirectly by regulating release of the hormone, gastrin, the stimulatory paracrine amine, histamine, and the inhibitory paracrine peptide, somatostatin. In the antrum, cholinergic and bombesin/GRP neurons activated by intraluminal proteins stimulate gastrin secretion directly and, in the case of cholinergic neurons, indirectly by eliminating the inhibitory influence of somatostatin (disinhibition). In turn, gastrin acts on adjacent somatostatin cells to restore the secretion of somatostatin. The dual paracrine circuit activated by antral neurons determines the magnitude of gastrin secretion. Low-level distention of the antrum activates, preferentially, VIP neurons that stimulate somatostatin secretion and thus inhibit gastrin secretion. Higher levels of distention activate predominantly cholinergic neurons that suppress antral somatostatin secretion and thus stimulate gastrin secretion. In the fundus, cholinergic neurons activated by distention or proteins stimulate acid secretion directly and indirectly by eliminating the inhibitory influence of somatostatin. The same stimuli activate bombesin/GRP and VIP neurons that stimulate somatostatin secretion and thus attenuate acid secretion. In addition, gastrin and fundic somatostatin influence acid secretion directly and indirectly by regulating histamine release. Acid in the lumen stimulates somatostatin secretion, which attenuates acid secretion in the fundus and gastrin secretion in the antrum.

Animals↗
PubMed1991

Paracrine actions of IGF binding proteins.

The paracrine mode of action for IGFs has been hypothesized on the basis of the finding that these peptides are synthesized ubiquitously. As IGFs circulate in very high concentrations (nearly 1 mg/l) they should have an endocrine function; moreover since the liver seems to be responsible for most of the circulating IGF-I it should be recognized that the basis of the "hormonal" IGF-I residues in the liver, whereas the extrahepatic synthesis provides support for local paracrine or autocrine actions. According to the endocrine hypothesis, the liver, which lacks IGF-I receptors, produces both IGF-I and IGF binding protein (IGFBP) and, possibly, the acid-labile subunit. All these components combine in the circulation, and only free IGF-I or small molecular weight complexes cross the capillary wall and reach the target cells. The paracrine hypothesis is based on the fact that fibroblasts are able to synthesize both IGF peptides and IGFBP, whereas keratinocytes are not, although they possess IGF receptors and are sensitive to IGF action. Since affinity of BP3 (which seems to be produced by peripheral fibroblasts) for IGF-I is higher than that of fibroblasts and, to a lesser degree, of keratinocytes, it is likely that IGF-I released from fibroblasts preferentially binds to BP3; the BP3-IGF-I complex reduces the autocrine effects on fibroblasts and preferentially directs the peptide binding to keratinocytes. The secretion of both IGFs and of IGF carrier proteins has been reported in several neoplastic epithelial cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Paracrine downregulation of Fc gamma RIII in human monocyte-derived macrophages induced by phagocytosis of nonopsonized particles.

Monocytes and macrophages can take up nonopsonized particles through a direct phagocytic process and IgG-coated particles through combined mechanisms of nonspecific phagocytosis and internalization mediated by specific Fc receptors for IgG (Fc gamma R) on the plasma membrane. In this study, we report the effect of phagocytosis of nonopsonized latex beads on the levels of expression of Fc gamma receptors in human monocyte-derived macrophages (MDM) as measured by flow cytometry (fluorescence-activated cell sorter [FACS]). Macrophages were exposed to green fluorescent 1-micron polystyrene beads before labeling for Fc gamma RI, Fc gamma R-II, and Fc gamma R-III, respectively, with 32.2, 2E1, and 3G8 monoclonal antibodies (MoAbs) and a phycoerythrin (PE)-conjugated secondary Ab to permit dual-channel analysis of fluorescence intensity by FACS. Macrophages that had phagocytosed at least one bead showed reduced levels of surface Fc gamma R-III but not Fc gamma R-I or Fc gamma R-II when compared with cells that had never been exposed to beads. Moreover, cells that were not in direct contact with beads, but that shared medium with cells that had phagocytosed beads also had reduced levels of Fc gamma R-III but not Fc gamma R-I or Fc gamma R-II, suggesting a cytokine-mediated mechanism of Fc gamma R-III downregulation. Phagocytosis of 1-micron beads alone stimulated macrophages to release tumor necrosis factor-alpha (TNF-alpha). The medium from macrophages phagocytosing beads could stimulate other macrophages not in direct contact with beads to release TNF-alpha as well, but such paracrine-triggered release could be reduced by more than 50% if the medium from the phagocytosing cells was first treated with a neutralizing anti-TNF-alpha antibody. Moreover, the paracrine downregulation of Fc gamma R-III described above could also be blocked if the neutralizing anti-TNF-alpha antibody was added to the medium of phagocytosing cells. Treatment of macrophages with recombinant human TNF-alpha in the absence of beads induced decreased levels of Fc gamma R-III but not of Fc gamma R-II. These results show that paracrine downregulation of Fc gamma R-III is mediated by a TNF-alpha-dependent mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗