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PubMed2003

Paracrine interactions of mammalian adipose tissue.

Adipose tissue develops in and/or around most lymphoid tissues in mammals and birds. Early reports of this widespread association and hypotheses for its functional basis were long ignored in the planning of in vitro studies and the interpretation of in vivo results. Biochemical studies on rodent tissues reveal many site-specific properties of adipocytes anatomically associated with lymph nodes and omental milky spots that equip them to interact locally with lymphoid cells. The paracrine interactions are strongest for the most readily activated lymph nodes and are modulated by dietary lipids. Perinodal adipocytes contribute less than those in the large nodeless depots to whole-body lipid supplies during fasting. Observations on wild animals show that perinodal adipose tissue is selectively conserved even in starvation but does not enlarge greatly in natural obesity. Such paracrine provisioning of peripheral immune responses improves their efficiency and emancipates activated lymphocytes from competition with other tissues for blood-borne nutrients. The relationship is found in extant protherians and metatherians, so it almost certainly arose early in the evolution of mammals, possibly as part of the metabolic reorganisation associated with homeothermy, viviparity, and lactation. Prolonged disruption to paracrine interactions between lymphoid and adipose tissue may contribute to the HIV-associated adipose redistribution syndrome, causing selective hypertrophy of the mesentery, omentum, and other adipose depots that contain much activated lymphoid tissue. Skeletal and cardiac muscle may also have paracrine relationships with anatomically associated adipose tissue, but interactions between contiguous tissues have not been demonstrated directly.

Adipose Tissue↗
PubMed2004

A paracrine signaling role for serotonin in rat taste buds: expression and localization of serotonin receptor subtypes.

Recent advances in peripheral taste physiology now suggest that the classic linear view of information processing within the taste bud is inadequate and that paracrine processing, although undemonstrated, may be an essential feature of peripheral gustatory transduction. Taste receptor cells (TRCs) express multiple neurotransmitters of unknown function that could potentially participate in a paracrine role. Serotonin is expressed in a subset of TRCs with afferent synapses; additionally, TRCs respond physiologically to serotonin. This study explored the expression and cellular localization of serotonin receptor subtypes in TRCs as a possible route of paracrine communication. RT-PCR was performed on RNA extracted from rat posterior taste buds with 14 prime sets representing 5-HT(1) through 5-HT(7) receptor subtype families. Data suggest that 5-HT(1A) and 5-HT(3) receptors are expressed in taste buds. Immunocytochemistry with a 5-HT(1A)-specific antibody demonstrated that subsets of TRCs were immunopositive for 5-HT(1A). With the use of double-labeling, serotonin- and 5-HT(1A)-immunopositive cells were observed exclusively in nonoverlapping populations. On the other hand, 5-HT(3)-immunopositive taste receptor cells were not observed. This observation, combined with other data, suggests 5-HT(3) is expressed in postsynaptic neural elements within the bud. We hypothesize that 5-HT release from TRCs activates postsynaptic 5-HT(3) receptors on afferent nerve fibers and, via a paracrine route, inhibits neighboring TRCs via 5-HT(1A) receptors. The ole of the 5-HT(1A)-expressing TRC within the taste bud remains to be explored.

Animals↗
PubMed2001

Cellular basis for paracrine regulation of ovarian follicle development.

Paracrine factors secreted by oocytes and somatic cells regulate many important aspects of early ovarian follicle development in mammals. From activation of dormant primordial follicles to selection of secondary follicles, locally acting factors have been identified that appear to exert important effects on the growth and differentiation of oocytes and granulosa cells. This article summarizes evidence to support a model for bi-directional paracrine communication that is based on developmental regulation of the delivery and reception of paracrine factors at the oocyte-granulosa cell interface. Transzonal projections that originate from granulosa cells and terminate at the oocyte plasma membrane provide a polarized means to orient the secretory organelles of somatic cells. Characterization of transzonal projections in follicles from normal and genetically modified mice reveals dynamic changes in the density and stability of transzonal projections. On the basis of new data analysing the orientation and cytoskeletal content of transzonal projections in mammalian oocytes, a model is proposed for regulation of paracrine growth factor secretion by follicle-stimulating hormone. These findings have immediate implications for ovarian hyperstimulation protocols and follicle culture models as related to the production of mammalian embryos by assisted reproductive technologies.

Animals↗
PubMed1998

Both autocrine and paracrine effects of transfected acidic fibroblast growth factor are involved in the estrogen-independent and antiestrogen-resistant growth of MCF-7 breast cancer cells.

To determine the extent to which autocrine effects of acidic fibroblast growth factor (FGF)-1 overexpression contribute to an increased malignant phenotype, FGF-1-transfected MCF-7 cells were retransfected with a FGF receptor (FGFR1) vector encoding a truncated dominant-negative receptor to inhibit autocrine FGF signal transduction. This transfection eliminated FGF signaling within the breast cancer cells without interfering with their ability to produce FGF-1, thereby allowing possible paracrine effects to still be observed in vivo. Truncated FGFR1 overexpression inhibited the acquired ability of FGF-1-overexpressing cells to form colonies in soft agar in estrogen-depleted or antiestrogen-containing medium. However, soft agar colony formation was still stimulated by estrogen treatment in cells expressing up to 6 x 10(5) truncated FGFR1 sites per cell. In vivo, truncated receptor expression severely inhibited the ability of the FGF-1-overexpressing cells to form tumors without estrogen in ovariectomized mice, indicating that the mitogenic effect of FGF-1 on the breast tumor cells was important in the estrogen-independent in vivo growth of these transfectants. However, rapid formation of large tumors was still observed in estrogen-supplemented mice injected with the truncated FGFR1-expressing cells, suggesting that the paracrine effects of FGF production could act in synergy with mitogenic effects mediated by estrogen. Truncated FGFR1-overexpressing cells also continued to form tumors in tamoxifen-treated mice, raising the possibility that the paracrine effects of FGF-1 expression may allow the partial agonist properties of this antiestrogen to be more readily observed. We conclude that autocrine effects of FGF-1 increase the ability of MCF-7 breast cancer cells to grow in vitro and in vivo under estrogen-depleted conditions but that paracrine effects of FGF-1 are also involved in the enhancement of tumor growth in estrogen-supplemented or tamoxifen-treated animals.

Animals↗
PubMed1996

Growth factor PDGF-B/v-sis confers a tumorigenic phenotype to human tumor cells bearing PDGF receptors but not to cells devoid of receptors: evidence for an autocrine, but not a paracrine, mechanism.

Numerous established human tumor lines co-express platelet-derived growth factor (PDGF) and cognate receptors, suggesting that an autocrine and/or paracrine growth mechanism may be a causal or contributing mechanism to their transformed phenotype. Indeed, it is known that a PDGF-autocrine system is functional in several established tumor lines, especially in human gliomas, and a model for a functional paracrine mechanism has been established in a human melanoma line. However, at least 168 human cell lines representing 26 different human tumor types have been reported to continuously express PDGF-A and/or -B chains, and 55 of these also express PDGF receptors. For the majority of these cases, the significance of co-expression and the relative roles of autocrine and paracrine mechanisms in transformation remains unclear. Here, we show that human glioblastoma T98G cells co-express PDGF-B/c-sis and moderate levels of the cognate beta-type PDGF receptor (PR-beta) but are not tumorigenic in athymic mice. In contrast, human breast carcinoma MCF-7 cells do not express PR-beta and are tumorigenic. Clonal lines of each cell type with greatly increased secretion of p16w(T98Gsis and MCF-7sis cells) were characterized. T98Gsis cells are 85% tumorigenic and occasionally develop pulmonary metastases, showing that endogenous PR-beta can mediate complete transformation upon sufficient stimulation. In contrast, MCF-7sis cells exhibit some growth slowing in vitro and an exactly proportional decrease in tumor growth rate. We conclude that a PDGF-autocrine, and not a paracrine, mechanism best accounts for the acquired tumorigenicity of T98Gsis cells, thereby emphasizing the potential significance of expression of even moderate levels of PR-beta by human tumor cells.

Animals↗
PubMed1993

Paracrine and autocrine growth mechanisms in tumor metastasis to specific sites with particular emphasis on brain and lung metastasis.

Once metastatic cells successfully seed at distant sites, their clinical detection and danger to the host are dependent on growth to form gross metastases. Metastatic tumor cells proliferate in response to local paracrine growth factors and inhibitors, and their growth also depends on production and responses to autocrine growth factors. A major organ-derived (paracrine) growth factor from lung tissue-conditioned medium has been isolated that differentially stimulates the growth of cells metastatic to brain or lung. Characterization of this mitogen demonstrated that it is a transferrin or a transferrin-like glycoprotein. Furthermore, antibodies to transferrin can remove significant growth activity from lung tissue-conditioned medium. Cells that are metastatic to brain or lung express greater numbers of transferrin receptors on their surfaces than cells that are poorly metastatic or metastatic to liver. Growth responses of metastatic cells and organ preferences of colonization appear to change during progression to more malignant states. At early stages of metastatic progression there is a tendency for many common malignancies to metastasize and grow preferentially at particular sites, suggesting that paracrine growth mechanisms may dominate the growth signals at this stage of progression. In contrast, at later stages of metastatic progression widespread dissemination to various tissues and organs occurs, and autocrine growth mechanisms may dominate the growth responses of metastatic cells. Ultimately, the progression of malignant cells to completely autonomous (acrine) states can occur, and at this stage of metastatic progression cell growth may be completely independent of autocrine and paracrine growth factors or inhibitors.

Animals↗
PubMed1992

Paracrine control of photomembrane removal.

Photomembrane turnover in vertebrate photoreceptors is regulated by light. Rod outer segments (ROS) shed membrane filled tips at light onset, during the coexistence of two light modulated processes: a dark priming factor and a light induction event. Transduction of these two signals is not direct but appears to involve the neural retina and diffusible paracrine molecules. I propose a model wherein three paracrines control this ROS tip shedding. Melatonin, a lipid soluble dark priming molecule, is synthesized in the dark by all photoreceptor cells, diffusing freely and separating the ROS disk membranes. A second paracrine, dopamine is released from the inner retina whenever light is absorbed by the 502 nm-cones, inhibiting melatonin synthesis. Third, a proposed trophic paracrine, "rostrophin", is released in the dark from internal horizontal cells, and stabilizes the photomembrane. Shedding occurs as rostrophin decreases in the presence melatonin; briefly at light onset or continuously in red or dim white light.

Animals↗
PubMed2000

Paracrine effects of angiotensin-converting-enzyme- and angiotensin-II-receptor- inhibition on transcapillary glucose transport in humans.

The paracrine renin-angiotensin-system (RAS) is increasingly recognized to play an important role in the regulation of both, regional vascular tone and regional glucose metabolism. To date, however, a selective investigation of paracrine RAS effects in an in vivo clinical setting was beyond technical reach. We here set out to selectively study the metabolic effects of paracrine RAS inhibition at different levels in healthy volunteers (n = 8). For this purpose bradykinin, enalaprilate and losartan were administered locally to the interstitial space fluid in skeletal muscle by means of reverse microdialysis and transcapillary glucose transport was measured simultaneously. During reverse microdialysis with bradykinin and enalaprilate a significant decrease in arterial-interstitial-gradient for glucose (AIG(glu)) was observed (from 1.49 +/- 0.08 mM to 0.12 +/- 0.63 mM (p = 0.018) for bradykinin and from 1.5 +/- 0.07 mM to 0.24 +/- 0.67 mM (p = 0.043) for enalaprilate). In contrast, losartan had no effect on AIG(glu). The changes in transcapillary glucose transport during bradykinin and enalaprilate administration were accompanied by significant increases in interstitial lactate levels which was most pronounced for bradykinin (from 0.14 +/- 0.01 mM to 0.40 +/- 0.07 mM, p = 0.018). We conclude that paracrine angiotensin-converting-enzyme (ACE) inhibition but not angiotensin II (AT-II) receptor blockade decreases AIG(glu) and facilitates transcapillary glucose transport due to an increase in interstitial bradykinin concentration. These results support the concept that blood pressure control with ACE-inhibitors but not with AT-II-receptor-antagonists has beneficial long term metabolic consequences in hypertensive, hyperinsulinemic subjects.

Adult↗
PubMed1986

Paracrine mechanisms involved in granulosa cell differentiation.

Since the heterogeneous development of individual follicles in a given ovary cannot be accounted for by changes in circulating gonadotropin levels, local modulatory factors play an important role in the paracrine control of follicular development. The important paracrine role of ovarian steroids has been well established. Oestrogen is important in the augmentation of gonadotropin action. High local concentration of oestrogens enhances the gonadotropin stimulation of aromatase activity, resulting in further increases in oestrogen production. The elevated local oestrogens in the follicular fluid are also capable of enhancing the FSH induction of LH receptors. Similar to oestrogens, local high concentrations of progesterone may enhance the gonadotropin stimulation of progesterone biosynthesis in granulosa and luteal cells. This positive autofeedback mechanism is believed to be important for the autonomy of luteal cell steroidogenesis. Ovarian actions of androgens are diverse. In the absence of FSH, androgens exert mainly negative effects at the follicular level by causing atresia and granulosa cell death, whereas in the presence of FSH, androgens augment FSH stimulation of progesterone and oestrogen biosynthesis. Since androgen and oestrogen appear to antagonize each other's actions, the ratio of these two steroids is important in determining the fate of an individual follicle. In contrast to ovarian steroids, the role of ovarian peptides as paracrine signals is less clear. In vitro studies clearly demonstrated that GnRH exerts both stimulatory and inhibitory actions on follicular functions, while IGF-I and VIP stimulate ovarian steroidogenesis. The actions of these peptides are presumably mediated through specific granulosa cell receptors that have been tentatively identified. It is presumed that GnRH and IGF-I may be produced by ovarian cells, while VIP may be derived from ovarian nerves. It is anticipated that new methodologies will be developed to study individual follicles as independent units, capable of synthesizing hormones, releasing them, and exerting local paracrine functions.

Androgens↗
PubMed1996

Paracrine coronary endothelial modulation of diastolic left ventricular function in man: implications for diastolic heart failure.

Coordinated release of relaxing and contracting factors from the endothelium modulates arterial distensibility. Recently, a similar release of the same and other factors from the coronary endothelium was shown to modulate myocardial performance in humans. This paracrine modulation of left ventricular (LV) performance by substances released from the coronary endothelium mainly affects diastolic LV function. This was evident from the reduction in end-systolic LV pressure, the earlier onset of LV relaxation and the increased LV diastolic distensibility observed in normal subjects during bi-coronary infusion of substance P. In experimental preparations, substance P elicited similar effects on diastolic LV function, which were attributed to a paracrine myocardial action of nitric oxide (NO) because they were absent after addition of hemoglobin. In normal subjects, the myocardial effects of NO were investigated during bi-coronary infusion of the NO-donor sodium nitroprusside and resembled the effects observed during bi-coronary infusion of substance P. This paracrine control of diastolic LV function by the coronary endothelium is influenced by substrate availability and by many neurohumoral substances, whose plasma levels are raised in heart failure. In transplant recipients, bi-coronary co-infusion of substance P and of L-arginine, the substrate for NO production, potentiated the fall in LV filling pressures. Pretreatment with intravenous dobutamine augmented the drop in LV end-systolic pressures observed during bi-coronary infusion of substance P. In isolated papillary muscles, a higher baseline myocardial c-GMP level, as induced by atrial natriuretic peptide, potentiates the negative inotropic and relaxation hastening effects of NO. In isolated ejecting guinea-pig hearts, an endothelin receptor antagonist improved diastolic LV function and this improvement implies paracrine myocardial action on diastolic LV function not only of NO but also of endothelin. Coronary endothelial control of myocardial function affects LV performance both acutely and chronically. An acute increase in heart rate augments release of NO because of coronary reactive hyperemia, lowers LV filling pressures thereby promoting subendocardial perfusion, and hastens LV relaxation thereby prolonging the diastolic time interval for coronary perfusion. Chronic changes in coronary endothelial function could also influence diastolic LV performance. Enhanced coronary endothelial NO release, as occurs during chronic exercise or pacing, could explain increased LV diastolic distensibility observed in athlete's heart and in tachycardia cardiomyopathy. Reduced endothelial NO release, as occurs with aging or after transplantation, could contribute to reduced LV diastolic distensibility in the elderly or in allograft recipients.

Coronary Vessels↗
PubMed1996

Pexicrine effects of basement membrane components on paracrine signaling by renal tubular cells.

Paracrine interactions between tubular epithelium and interstitial cells have been assumed to be mediated largely by soluble cytokines. While the role of extracellular matrix (ECM) and matrix metalloproteinases (MMPs) in modifying cell function is widely appreciated, the role of the renal tubular basement membrane in modulation of tubulointerstitial function has not been studied. To establish whether those components of the ECM which support tubular epithelial cells also influence cell function (that is, a pexicrine effect), we studied their effects on paracrine signaling between epithelium and fibroblasts. Primary cultures of rat renal proximal tubular epithelial cells (PTE) were cultured on laminin (LN), collagen types-IV and -I (COL-IV, COL-I) and fibronectin (FN). PTE attained confluence more rapidly when grown on LN = COL-IV > COL-I = FN = plastic. On all substrates PTE produced the MMPS, gelatinase-A and -B and collagenase with an apparent increase in gelatinase-A and -B production when cultured on LN. MMPs were found to be secreted both apically and basally with basal secretion predominating, except on LN where secretion was primarily from the apical surface. Cultures of rat renal cortical interstitial fibroblasts were established and characterized. Cortical fibroblasts (CF) were found to secrete gelatinase-A and collagenase. Conditioned medium (CM) from PTE cultured on COL-IV stimulated proliferation of CF but proliferation was unaltered by CM from PTE grown on other substrates. By contrast, co-culture of PTE on LN with CF suppressed collagenase and gelatinase activity in both cell types, indicating a bi-directional, paracrine modulation of MMP production. Thus in the tubulointerstitium, the BM components LN and COL-IV not only fulfill a structural role but act as signaling molecules with differential effects which modify the function of the tubular epithelium and its paracrine interaction with adjacent fibroblasts. The initiation of interstitial fibrosis induced by injury to the tubular basement membrane may reside in the perturbation of this interaction.

Animals↗
PubMed1998

Paracrine stimulation of human renal fibroblasts by proximal tubule cells.

UNLABELLED: Paracrine stimulation of human renal fibroblasts by proximal tubule cells. BACKGROUND: Interstitial fibrosis strongly predicts the degree and progression of renal failure in human renal disorders. Since active fibrosis tends to initially occur in a peritubular distribution, the possibility that human proximal tubule cells (PTC) relay fibrogenic signals to neighboring cortical fibroblasts was examined in vitro. METHODS: Cell proliferation (cell counts and thymidine incorporation), total collagen synthesis (proline incorporation), matrix metalloproteinase (MMP) activity (gelatin zymography), and autocrine secretion of insulin-like growth factor-I (IGF-I) were measured in primary cultures of human cortical fibroblasts cocultured with PTC or exposed to PTC-conditioned media (PTCCM). RESULTS: Cell numbers and thymidine incorporation rates were increased in cortical fibroblasts cocultured with PTC (136.4+/-7.3% and 119.3+/-8.2% of control values, respectively, P < 0.05) or incubated in PTC-CM (114.0+/-5.9%, P < 0.05 and 146.7+/-13.3%, P < 0.05, respectively). PTC-CM stimulated cortical fibroblast collagen synthesis (13.5+/-1.0% vs. 10.8+/-0.7%, respectively, N = 24, P < 0.05) and MMP-2 and MMP-9 secretion. Cortical fibroblast secretion of IGF-I binding protein-3 (IGFBP-3), which in turn modulates the autocrine and paracrine actions of IGF-I, was enhanced in the presence of PTC-CM compared with control (1162.2+/-94.2 vs. 969.1+/-58.9 ng/mg protein/day, P < 0.05), but no change was observed in cortical fibroblast secretion of IGFBP-2 (260.9+/-38.8 vs. 290.9+/-36.6 ng/mg protein/day, P = NS) or IGF-I (56.7+/-6.6 vs. 57.0+/-6.8 ng/mg protein/day, P = NS). Human PTC secreted transforming growth factor-beta1 (TGF-beta1) and the AB heterodimer of platelet-derived growth factor (PDGF-AB) in a time-dependent fashion and the augmentation of cortical fibroblasts mitogenesis, collagen synthesis and IGFBP-3 secretion induced by PTC-CM was replicated by exogenous TGF-beta1 and PDGF. Furthermore, the stimulatory effects of PTC on cortical fibroblasts were potentiated in transiently acidified PTC-CM (which activated latent TGF-beta1), and were abrogated by neutralizing antibodies specifically directed against TGF-beta1 and PDGF-AB. Cortical fibroblasts in turn released a soluble factor(s) into cortical fibroblast-conditioned media that reciprocally stimulated PDGF-AB production by PTC (4.79+/-1.55 vs. 0.78+/-.06 ng/mg protein/day, P < 0.05). CONCLUSIONS: PTC modulate the biological behavior of neighboring cortical fibroblasts in the human kidney through paracrine mechanisms, which include the production and release of PDGF-AB and TGF-beta1. Renal insults that result in proximal tubule injury may perturb this paracrine interaction, thereby culminating in excessive fibroblast proliferation and interstitial fibrosis.

Adult↗
PubMed1995

Paracrine cell to cell interactions determine the effects of pituitary adenylate cyclase activating polypeptide (PACAP) on in vitro prolactin release from rat pituitary cells.

In static cultures of dispersed rat pituitary cells and in the reverse hemolytic plaque assay PACAP inhibits prolactin (Prl) secretion, while in vivo application of PACAP stimulates Prl release in rats. To elucidate the mechanism of this contradictory action, we compared the in vitro effects of PACAP on Prl secretion in cultures of dispersed or reaggregated cells and in pituitary fragments. While in monolayer cultures Prl release was inhibited by PACAP, in cultures of aggregated cells and in pituitary fragments Prl release was stimulated. Dopamine (DA) inhibited Prl release in either type of culture. PACAP also stimulated interleukin 6 (IL6) release under each of the experimental conditions. We conclude that PACAP has a direct inhibitory action on lactotropes. In addition, PACAP may induce the release of a paracrine acting factor within the pituitary which stimulates Prl release and which may be IL6. In the intact pituitary tissue and in reaggregated cells this paracrine factor stimulates Prl release more potently than PACAP directly inhibits Prl secretion resulting in a net effect of enhanced hormone release. In monolayer cultures, however, the direct inhibition is dominant, because the stimulatory paracrine factor is diluted in the culture medium. Therefore we suggest that paracrine cell to cell communication is crucial for the action of PACAP on Prl release.

Animals↗
PubMedDate not supplied

Paracrine factors in adult rat testis gonadotrophin control of opioids and LHRH like peptide.

A paracrine regulation involves agents which are produced by one cell type and act on an other one within an organ. In rodent testis, local control mechanisms modulate the actions of the gonadotrophins according to local requirements. Two groups of peptides-opioids and testicular LHRH are defined as paracrine factors and in vivo they are both modified by HCG. In vitro, after HCG exposure, we first localized an opioid like material in Sertoli cells cytoplasma by immunohistochemistry. This material is detected in freeze dried homologous culture media using a dot immunobinding technique. With a longer HCG exposure, an LHRH like material is then visualized in the basal compartment of the Sertoli cells and it is detected in freeze dried homologous culture media by the same technical procedure than for opioid material. By adding synthetic enkephalins to culture medium, we obtain the same results as with the endogenous opioid material, excreted after HCG addition. If naloxone a potent opiate antagonist, is added to the culture medium previously to HCG or enkephalins, the Sertoli cells cytoplasma are no more immunoreactives with the anti-enkephalin serum and no LHRH material is neither visualized by immunohistochemical technique neither detected in culture media. We conclude that testicular opioids, synthetized by the Leydig cells and which have specific Sertoli cells receptors are one Leydig-Sertoli paracrine communication factor. One way of response to their receptor fixation is the synthesis and excretion by Sertoli cells of testicular LHRH. This one is known to act on Leydig cells via specific receptors and it is one Sertoli-Leydig cells paracrine communication factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Paracrine mediators of endometrial matrix metalloproteinase expression: potential targets for progestin-based treatment of endometriosis.

The endometrial lining of the human uterus is a highly specialized, steroid-sensitive tissue. Throughout the reproductive years, the endometrium undergoes dramatic cycles of growth, differentiation, and breakdown under the influence of ovarian steroids. In response to changes in steroid exposure throughout the menstrual cycle, the endometrium produces an array of bioactive growth factors and other cytokines that are critical components of paracrine communication. For example, cell-cell communication via paracrine factors directs the expression of matrix metalloproteinases (MMPs), enzymes that mediate tissue remodeling during the menstrual cycle. The disease endometriosis is thought to occur as a consequence of retrograde menstruation, and MMPs appear to contribute to the establishment and progression of ectopic endometrial growth in the peritoneal cavity. Although the risk for developing endometriosis is linked to a woman's steroid exposure, locally produced paracrine factors can modify steroid action on multiple gene targets, including the MMPs. Estrogen-associated growth factors as well as inflammatory cytokines are potent stimulators of MMP expression and may contribute to the ability of endometrial fragments to invade the peritoneal surface and establish ectopic sites of growth. In contrast, paracrine factors associated with progesterone action during early pregnancy inhibit MMP expression and prevent ectopic endometrial growth in an experimental model. For example, locally produced retinoic acid and transforming growth factor-beta (TGF-beta) act in concert with progesterone to suppress MMPs, while enhancing expression of MMP inhibitors (TIMPs) during endometrial differentiation. Targeting pregnancy-associated factors that inhibit endometrial-specific MMP expression and action may enhance the effectiveness of progestin-related treatments for endometriosis.

Endometriosis↗
PubMed1998

Galanin is a paracrine inhibitor of gonadotroph function in the female rat.

Recent evidence suggests that pituitary galanin synthesized in the lactotroph is a paracrine regulator of lactotroph proliferation and PRL secretion and that these effects are mediated via a pituitary-specific galanin receptor, GAL-R2(orig.). At this receptor subtype, the galanin fragment 3-29 is fully active, in contrast to both the cloned GAL-R1 and GAL-R2, at which this fragment is inactive. Since paracrine communication has been demonstrated between pituitary gonadotrophs and lactotrophs, we investigated the hypothesis that galanin is also a paracrine regulator of gonadotroph function. Galanin attenuated LHRH-stimulated LH release in a dose-dependent manner in monodispersed rat anterior pituitaries harvested at proestrus (LHRH 100 nM, 10.7 +/- 0.2 ng/ml(-1) x 4 h vs. LHRH 100 nM + 1 microM porcine galanin (pGal), 7.0 +/- 0.2 ng/ml(-1) x 4 h; P < 0.01; i.e. 37% reduction). Galanin had similar suppressive effects on FSH release. Galanin, also dose-dependently, attenuated the LHRH-stimulated LH release from perifused proestrous rat pituitary fragments. pGal (1 microM) reduced the stimulated LH release by 80%, [area under the curve (AUC), LHRH 100 nM, 713 +/- 149 vs. LHRH 100 nM + 1 microM pGal, 131 +/- 7 ng/min x ml(-1) x 4 h; P < 0.02]. In addition, galanin 3-29, the specific GAL-R2(orig.) receptor agonist, inhibited LHRH-stimulated LH release from perifused proestrous rat pituitary fragments [AUC, LHRH 100 nM, 642 +/- 77 ng/min x ml(-1) vs. LHRH 100 nM + pGal 1-29, 206 +/- 44 ng/min x ml(-1) (P < 0.02); and LHRH 100 nM + pGal 3-29, 310 +/- 19 ng/min x ml(-1) (P < 0.02)]. Immunoblockade with specific galanin antiserum potentiated the LHRH-stimulated release of LH by 48% from perifused proestrous rat pituitary fragments (AUC, LHRH 100 nM + galanin antiserum, 721 +/- 65 ng/min x ml(-1) vs. LHRH 100 nM alone or with nonimmune antiserum, 489 +/- 33 ng/min x ml(-1) or 545 +/- 46 ng/min x ml(-1), P < 0.05). This data suggests that galanin may act as a paracrine agent via the pituitary-specific GAL-R2(orig.) to inhibit gonadotroph function.

Animals↗
PubMed1995

Autocrine and paracrine regulation of neoplastic cell growth in hairy cell leukemia.

Hairy cell leukemia (HCL), a rare haematological disorder of B-cell origin, mainly presents with bone marrow infiltration, haematopoietic insufficiency, and splenomegaly. In some cases, osteolytic lesions can be observed. Many of these clinical features, especially haematopoietic insufficiency and osteolytic lesions are likely to be caused by soluble factors, such as cytokines. There is evidence that these factors are produced by the malignant hairy cells themselves, suggesting a paracrine pathway. The importance of autocrine as well as paracrine growth loops in growth regulation of HCL-cells is supported by a series of excellent studies, performed within the last few years. It could be clearly shown that cytokines are involved in this autocrine and paracrine regulatory process. The most important cytokines which should be mentioned in this respect are tumor necrosis factor alpha, (TNF alpha). Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-6 (IL-6) and B-cell-growth factor (BCGF). The role of other factors such as viruses and oncogenes remains rather unclear. Nevertheless, recent data suggest that the c-fms, which encodes for the macrophage colony stimulating factor (M-CSF) may be involved in the pathophysiological control of HCL growth. In this review, we summarise the important data and studies performed recently which shed light on the complex network of autocrine and paracrine growth regulation of HCL.

Cell Division↗
PubMed1999

Paracrine immunotherapy with interleukin-2 and local chemotherapy is synergistic in the treatment of experimental brain tumors.

Potent immune responses against malignant brain tumors can be elicited by paracrine intracranial (i.c.) immunotherapy with interleukin (IL)-2. Additionally, i.c. delivery of carmustine via biodegradable polymers has been shown to significantly prolong survival in both animal models and clinical trials. In this study, we show that the combination of paracrine immunotherapy, with nonreplicating genetically engineered tumor cells that produce IL-2, and local delivery of chemotherapy by biodegradable polymers prolongs survival in a synergistic manner in mice challenged intracranially with a lethal murine brain tumor. Animals receiving IL-2-transduced cells and polymers containing 10% 1,3-bis(2-chloroethyl)-1-nitrosourea had significantly improved survival compared with animals receiving IL-2-transduced cells or 10% 1,3-bis(2-chloroethyl)-1-nitrosourea alone. Median survival for the control group was 19 days. Survival in animals receiving IL-2-transduced cells and 1% carboplatin-containing polymers was also significantly improved compared with either therapy alone. Histopathological examination on day 14 of animals receiving combination treatment showed rare degenerating tumor cells. In addition to tissue necrosis surrounding the polymer, a marked inflammatory reaction was observed. In long-term survivors (all animals receiving combination treatment), no tumor was observed and the inflammatory reaction was completely resolved. The brains of animals receiving combination therapy showed both tissue necrosis due to local chemotherapy and strong inflammation due to paracrine immunotherapy. The demonstration of synergy between paracrine IL-2 and local i.c. delivery of antineoplastic drugs is novel and may provide a combined treatment strategy for use against both primary and metastatic i.c. tumors.

Adjuvants, Immunologic↗