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Results for “augmented feedback”

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PubMed1981

Interaction of lactoferrin, monocytes, and T lymphocyte subsets in the regulation of steady-state granulopoiesis in vitro.

Colony-stimulating activities (CSA) are potent granulopoietic stimulators in vitro. Using clonogenic assay techniques, we analyzed the degree to which mononuclear phagocytes and T lymphocytes cooperate in the positive (production/release of CSA) and feedback (inhibition of CSA production/release) regulation of granulopoiesis. We measured the effect of lactoferrin (a putative feedback regulator of CSA production) on CSA provision in three separate assay systems wherein granulocyte colony growth of marrow cells from 22 normal volunteers was stimulated by (a) endogenous CSA-producing cells in the marrow cells suspension, (b) autologous peripheral blood leukocytes in feeder layers, and (c) medium conditioned by peripheral blood leukocytes. The CSA-producing cell populations in each assay were varied by using cell separation techniques and exposure of isolated T lymphocytes to methylprednisolone or to monoclonal antibodies to surface antigens and complement. We noted that net CSA production increased more than twofold when a small number of unstimulated T lymphocytes were added to monocyte cultures. Lactoferrin's inhibitory effect was also T lymphocyte dependent. The T lymphocytes that interact with monocytes and lactoferrin to inhibit CSA production are similar to those that augment CSA production because their activities are neither genetically restricted not glucocorticoid sensitive, and both populations express HLA-DR (Ia-like) and T3 antigens but not T4 or T8 antigens. These findings are consistent with results of our studies on the mechanism of lactoferrin's inhibitory effect with indicate that mononuclear phagocytes produce both CSA and soluble factors that stimulate T lymphocytes to produce CSA, and that lactoferrin does not suppress monocyte CSA production, but does completely suppress production or release by monocytes of those factors that stimulate T lymphocytes to produce CSA. We conclude that mononuclear phagocytes and a subset of T lymphocytes exhibit important complex interactions in the regulation of granulopoiesis.

Bone Marrow Cells↗

PubMed2004

Stochastic optimal therapy for enhanced immune response.

Therapeutic enhancement of humoral immune response to microbial attack is addressed as the stochastic optimal control of a dynamic system. Without therapy, the modeled immune response depends upon the initial concentration of pathogens in a simulated attack. Immune response can be augmented by agents that kill the pathogen directly, that stimulate the production of plasma cells or antibodies, or that enhance organ health. Using a generic mathematical model of immune response to the infection (i.e., of the dynamic state of the system), previous papers demonstrated optimal (open-loop) and neighboring-optimal (closed-loop) control solutions that defeat the pathogen and preserve organ health, given initial conditions that otherwise would be lethal [Optimal Contr. Appl. Methods 23 (2002) 91, Bioinformatics 18 (2002) 1227]. Therapies based on separate and combined application of the agents were derived by minimizing a quadratic cost function that weighted both system response and drug usage, providing implicit control over harmful side effects. Here, we focus on the effects that corrupted or incomplete measurements of the dynamic state may have on neighboring-optimal feedback control. Imperfect measurements degrade the precision of feedback adjustments to therapy; however, optimal state estimation allows the feedback strategy to be implemented with incomplete measurements and minimizes the expected effects of measurement error. Complete observability of the perturbed state for this four state example is provided by measurement of four of the six possible pairs of two variables, either set of three variables, or all four variables. The inclusion of state estimation extends the applicability of optimal control theory for developing new therapeutic protocols to enhance immune response.

Anti-Infective Agents↗

PubMed1997

Insulin-induced mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) attenuates insulin-stimulated MAP kinase activity: a mechanism for the feedback inhibition of insulin signaling.

Insulin signaling involves the transient activation/inactivation of various proteins by a cycle of phosphorylation/dephosphorylation. This dynamic process is regulated by the action of protein kinases and protein phosphatases. One family of protein kinases that is important in insulin signaling is the mitogen-activated protein (MAP) kinases, whose action is reversed by specific MAP kinase phosphatases (MKPs). Insulin stimulation of Hirc B cells overexpressing the human insulin receptor resulted in increased MKP-1 mRNA levels. MKP-1 mRNA increased in a dose-dependent manner to a maximum of 3- to 4-fold over basal levels within 30 min, followed by a gradual return to basal. The mRNA induction did not require the continuous presence of insulin. The induction of MKP-1 protein synthesis followed MKP-1 mRNA induction; MKP-1 protein was maximally expressed after 120 min of insulin stimulation. MKP-1 mRNA induction by insulin required insulin receptor tyrosine kinase activity, since overexpression of an altered insulin receptor with impaired intrinsic tyrosine kinase activity prevented mRNA induction. Forskolin, (Bu)2-cAMP, 8-bromo-cAMP, and 8-(4-chlorophenylthio)-cAMP increased the MKP-1 mRNA content moderately above basal. These agents also augmented the insulin-stimulated expression of MKP-1 mRNA. However, in some cases the increase in MKP-1 mRNA expression was less than additive. Nevertheless, these results indicate that multiple signaling motifs might regulate MKP-1 expression and suggest another mechanism for the attenuation of insulin-stimulated MAP kinase activity by cAMP. Overexpression of MKP-1 in Hirc B cells inhibited both insulin-stimulated MAP kinase activity and MAP kinase-dependent gene transcription. The results of these studies led us to conclude that insulin regulates MKP-1 and strongly suggest that MKP-1 acts as a negative regulator of insulin signaling.

Animals↗

PubMed2000

The role of CD23 on allergen-induced IgE levels, pulmonary eosinophilia and bronchial hyperresponsiveness in mice.

BACKGROUND: The role of Immunoglobulin (Ig)E in inflammation is the subject of considerable study and a number of studies have shown conflicting evidence for its role in eosinophil recruitment and bronchial hyperresponsiveness in a number of murine models. The low affinity IgE receptor, CD23, is known to act as a negative regulator of IgE production and we have used knockout mice deficient in CD23 to investigate the role of IgE in eosinophil recruitment and bronchial hyperresponsiveness in a murine model of airway inflammation. OBJECTIVE: To study the role of the low affinity FcepsilonII receptor, CD23 in IgE production, lung inflammation and bronchial hyperresponsiveness. METHODS: Wild-type and CD23 knockout C57Bl/6 mice (CD23-/-) were immunized by intraperitoneal injection with ovalbumin on days 0 and 14 and challenged with aerosolized antigen on day 21 for a period of up to 1 week. Blood samples, bronchoalveolar lavage and lung tissue samples were obtained to determine serum IgE levels and inflammatory cell numbers, respectively. Furthermore, airway resistance was measured to increasing concentrations of aerosolized 5-hydroxytryptamine in order to evaluate the effect of CD23 deficiency on bronchial hyperresponsiveness to antigen challenge. RESULTS: Sensitization of wild-type C57Bl/6 mice to ovalbumin resulted in elevated levels of total serum IgE and ovalbumin-specific IgE, which was significantly augmented in CD23 knockout C57Bl/6 mice (CD23-/-). A significant increase in the percentage of eosinophils recovered in bronchoalveolar lavage fluid from wild-type and CD23-/- mice was observed 24 h following 3 or 7 days aerosol exposure with ovalbumin (10 mg/mL). At 3 days, the increase in the percentage of eosinophils was significantly greater in CD23-/- groups. Immunohistochemical analysis of lungs sections revealed the presence of CD3+, CD4+ and CD23+ cells in wild-type mice but a lack of immunofluorescence of CD23+ cells in CD23-/- mice. In wild-type ovalbumin-immunized mice, bronchial hyperresponsiveness to aerosolized 5-hydroxytryptamine was observed following a 3-day antigen challenge, which was significantly greater in CD23-/- ovalbumin-immunized mice. CONCLUSION: These studies demonstrate that CD23-/- mice have increased capacity to produce IgE consistent with the view of a negative feedback role for membrane-bound CD23 and under such conditions, may account for the greater numbers of eosinophils recruited to the airways and bronchial hyperresponsiveness observed following acute but not chronic antigen challenge.

Allergens↗

PubMed1996

Fasting as a metabolic stress paradigm selectively amplifies cortisol secretory burst mass and delays the time of maximal nyctohemeral cortisol concentrations in healthy men.

Serum cortisol concentrations are increased in fasted or malnourished human subjects. The dynamic mechanisms underlying this adaptive response have been investigated in eight normal men by analyzing serum cortisol concentrations measured in blood obtained at 5-min intervals over 24 h on a control (fed) day and on the fifth day of a fast (water only) assigned in randomized order. A multiple parameter deconvolution method was used to simultaneously resolve endogenous cortisol secretion and half-life. Five days of fasting induced a 1.8-fold increase in the 24-h endogenous cortisol production rate (fed, 2504 +/- 308; fasted, 4528 +/- 488 nmol/L distribution volume; P < 0.006). This enhanced cortisol production rate was accounted for by a 1.6-fold increase in the mass of cortisol secreted per burst (fed, 115 +/- 12.1; fasted, 183 +/- 17.3 nmol/L; P < 0.02). Cortisol secretory event amplitudes (maximal rates of cortisol release attained within a burst) increased in seven of eight men, and mean secretory burst durations remained unchanged by fasting. Moreover, the number of computer-resolved cortisol secretory bursts per 24 h (fed, 22 +/- 1.4; fasted, 25 +/- 2.0; P = NS) and the interburst interval (fed, 65 +/- 4.0; fasted, 57 +/- 4.4 min) did not change significantly during a 5-day fast. The calculated half-life of endogenous cortisol was not significantly altered by fasting (fed, 108 +/- 9.7; fasted, 129 +/- 11 min). There was no significant change in the nyctohemeral pattern of varying adrenocortical secretory burst frequency in response to fasting. However, the mean (mesor) mass of glucocorticoid secreted per burst over 24 h rose significantly in response to fasting. In addition, by cosinor analysis, maximal serum cortisol concentrations occurred (95% confidence intervals) between 0930-1334 h in the fed state and between 1116-1612 h in the fasted state (P < 0.04). Fasting augmented the mesor (average value about which the diurnal rhythm oscillates; P < 0.0008 compared with fed state) and the amplitude (P < 0.04) of the 24-h serum cortisol concentration profile. Linear regression analysis disclosed a significant inverse relationship between mean serum cortisol and GH concentrations in fasted men (r = -0.76; P < 0.02). In conclusion, the present data indicate that starvation-induced enhancement of cortisol secretion in young healthy men is mediated by an increased glucocorticoid secretory burst mass, rather than changes in secretory burst frequency or duration or in cortisol half-life. In addition, fasting modifies the diurnal secretory pattern of cortisol by delaying maximal serum concentrations to the early afternoon. The inverse relationship between serum cortisol and GH responses to fasting suggests differential regulation of the corticotropic and somatotropic axis by the metabolic stress of fasting and/or feedback interactions between these two axes when they are both activated.

Adult↗

PubMed2006

Bradykinin augments insulin-stimulated glucose transport in rat adipocytes via endothelial nitric oxide synthase-mediated inhibition of Jun NH2-terminal kinase.

An increase in bradykinin has been suggested to contribute to the enhanced insulin sensitivity observed in the presence of ACE inhibitors. To investigate a potential direct, nonvascular effect on an insulin target tissue, the effect of bradykinin on glucose uptake and insulin signaling was studied in primary rat adipocytes. Whereas basal glucose uptake was not altered, bradykinin augmented insulin-stimulated glucose uptake twofold, which was blocked by HOE-140, a bradykinin B2 receptor antagonist. The bradykinin effect on glucose uptake was nitric oxide (NO) dependent, mimicked by NO donors and absent in adipocytes from endothelial NO synthase-/- mice. Investigation of insulin signaling revealed that bradykinin enhanced insulin receptor substrate-1 (IRS-1) Tyr phosphorylation, Akt/protein kinase B phosphorylation, and GLUT4 translocation. In contrast, insulin-stimulated extracellular signal-regulated kinase1/2 and Jun NH2-terminal kinase (JNK) activation were decreased in the presence of bradykinin, accompanied by decreased IRS-1 Ser307 phosphorylation. Furthermore, bradykinin did not enhance insulin action in the presence of the JNK inhibitor, SP-600125, or in adipocytes from JNK1-/- mice. These data indicate that bradykinin enhances insulin sensitivity in adipocytes via an NO-dependent pathway that acts by modulating the feedback inhibition of insulin signaling at the level of IRS-1.

Adipocytes↗

PubMed2006

Dual ligand stimulation of RAW 264.7 cells uncovers feedback mechanisms that regulate TLR-mediated gene expression.

To characterize how signaling by TLR ligands can be modulated by non-TLR ligands, murine RAW 264.7 cells were treated with LPS, IFN-gamma, 2-methyl-thio-ATP (2MA), PGE(2), and isoproterenol (ISO). Ligands were applied individually and in combination with LPS, for 1, 2, and 4 h, and transcriptional changes were measured using customized oligo arrays. We used nonadditive transcriptional responses to dual ligands (responses that were reproducibly greater or less than the expected additive responses) as a measure of pathway interaction. Our analysis suggests that cross-talk is limited; <24% of the features with significant responses to the single ligands responded nonadditively to a dual ligand pair. PGE(2) and ISO mainly attenuated, while 2MA enhanced, LPS-induced transcriptional changes. IFN-gamma and LPS cross-regulated the transcriptional response induced by each other: while LPS preferentially enhanced IFN-gamma-induced changes in gene expression at 1 h, IFN-gamma signaling primarily attenuated LPS-induced changes at 4 h. Our data suggest specific cross-talk mechanisms: 1) LPS enhances the expression of IFN-gamma-response genes by augmenting STAT1 activity and by activating NF-kappaB, which synergizes with IFN-gamma-induced transcriptional factors; 2) IFN-gamma attenuates the late LPS transcriptional response by increasing the expression of suppressor of cytokine signaling 1 and cytokine-inducible SH2-containing protein expression; 3) 2MA modulates LPS secondary transcriptional response by increasing IFN-beta and inhibiting IL-10 gene expression; 4) PGE(2) and ISO similarly regulate the LPS transcriptional response. They increase IL-10 transcription, resulting in attenuated expression of known IL-10-suppressed genes.

Adenosine Triphosphate↗

PubMed1991

Retinoic acid potentiates interleukin-1- and fibroblast growth factor-induced human synovial fibroblast proliferation.

All trans-retinoic acid (ATRA) and related compounds, at concentrations ranging from 10(-8) to 10(-6) M, augmented the proliferation of human synovial fibroblasts (HSN) stimulated by human interleukin-1 alpha or -beta (IL-1 alpha, IL-beta) and both the acidic and basic forms of fibroblast growth factor (FGFa, FGFb). In contrast, ATRA had no effect on human tumor necrosis factor alpha (TNF alpha)-induced HSN proliferation. The potentiation of HSN proliferation was completely dependent on the presence of IL-1 or FGF since HSN were unresponsive to ATRA alone. The mechanism by which ATRA enhances IL-1-induced HSN proliferation does not appear mediated by changes in the affinity or number of IL-1 receptors expressed by HSN; however, treatment with dexamethasone (DEX, 10(-6)M) resulted in a twofold increase in IL-1 receptor number. ATRA inhibited both IL-1 beta- and TNF alpha-induced secretion of prostaglandin-E2 (PGE2), a potent feedback inhibitor of cytokine-stimulated HSN proliferation. However, the synergistic effect of ATRA on IL-1- or FGF-induced proliferation did not appear related to the secretion of cyclooxygenase products since ATRA had no effect on TNF alpha-induced HSN proliferation and indomethacin was included in all HSN proliferation experiments. The results of this study suggest that ATRA may contribute to the pathology of chronic arthritic disease by potentially causing increased growth of the joint-destroying pannus.

Cell Division↗

PubMed2006

Adenosine restores angiotensin II-induced contractions by receptor-independent enhancement of calcium sensitivity in renal arterioles.

Adenosine is coupled to energy metabolism and regulates tissue blood flow by modulating vascular resistance. In this study, we investigated isolated, perfused afferent arterioles of mice, which were subjected to desensitization during repeated applications of angiotensin II. Exogenously applied adenosine restores angiotensin II-induced contractions by increasing calcium sensitivity of the arterioles, along with augmented phosphorylation of the regulatory unit of the myosin light chain. Adenosine restores angiotensin II-induced contractions via intracellular action, because inhibition of adenosine receptors do not prevent restoration, but inhibition of NBTI sensitive adenosine transporters does. Restoration was prevented by inhibition of Rho-kinase, protein kinase C, and the p38 mitogen-activated protein kinase, which modulate myosin light chain phosphorylation and thus calcium sensitivity in the smooth muscle. Furthermore, adenosine application increased the intracellular ATP concentration in LuciHEK cells. The results of the study suggest that restoration of the angiotensin II-induced contraction by adenosine is attributable to the increase of the calcium sensitivity by phosphorylation of the myosin light chain. This can be an important component of vascular control during ischemic and hypoxic conditions. Additionally, this mechanism may contribute to the mediation of the tubuloglomerular feedback by adenosine in the juxtaglomerular apparatus of the kidney.

Adenosine↗

PubMed2002

The effects of knowledge of performance and cognitive strategies on motor skill learning in children with cerebral palsy.

PURPOSE: The purpose of this research was to examine the effects of presenting augmented information to children with cerebral palsy during practice of a novel motor skill. METHODS: Single-subject designs with nonconcurrent baselines were used to study improvements in performance. Thirteen children with cerebral palsy were randomly assigned to one of three practice protocols and performed 36 ten-second trials to learn to move a Pedalo, a therapeutic exercise vehicle, backward. Each protocol involved a variable mix of practice under the following conditions: no augmented information, knowledge of performance, and knowledge of performance enhanced by a cognitive strategy. Performance was measured by changes in backward displacement (cm) of the Pedalo across trials. RESULTS: All 13 subjects demonstrated improvement in performance across phases. However, only eight subjects (62%) demonstrated a significant improvement in performance when the baseline and retention phases were compared. Of these eight subjects, one demonstrated significant improvement in performance with practice alone, two when provided with knowledge of performance, and five when provided with knowledge of performance and a cognitive strategy. CONCLUSIONS: This study suggests that children with cerebral palsy benefit greatly from practice of motor tasks and that some of these children may benefit from the use of cognitive strategies to enhance the role of knowledge of performance during practice of motor skills. However, sufficient time is required to successfully integrate the feedback into performance.

Journal Article↗

PubMed2005

Acute injections of brain-derived neurotrophic factor in a vocal premotor nucleus reversibly disrupt adult birdsong stability and trigger syllable deletion.

Behavioral variability serves an essential role in motor learning by enabling sensory feedback to select those motor patterns that minimize error. Birds use auditory feedback to learn how to sing, and their songs lose variability and become highly stereotyped, or crystallized, at the end of a sensitive period for sensorimotor learning. The molecular cues that regulate song variability are not well understood. In other systems, neurotrophins, and brain-derived neurotrophic factor (BDNF) in particular, can mediate various forms of neural plasticity, including sensitive period neural circuit plasticity and activity-dependent synapse formation, and may also influence learning and memory. Here, we have tested the hypothesis that neurotrophin expression in the robust nucleus of the arcopallium (RA), the telencephalic output controlling song, regulates song variability. BDNF and its receptor trkB are expressed in RA, and BDNF expression in RA appears to be highest in juveniles, when song is most variable and plastic, and synapse density highest. Thus, song variability and synaptic connectivity could be enhanced by augmented expression of BDNF in RA. In support of this idea, we found that BDNF injections into the adult RA induced the re-expression of juvenile-like phenotypes, including song variability and an increased synaptic density in RA. Furthermore, BDNF treatment also induced vocal plasticity, characterized by syllable deletions and persistent changes to the song patterns. These results suggest that endogenous BDNF could be a molecular regulator of the song variability essential to vocal plasticity and, ultimately, to song learning.

Animals↗

PubMed2000

Limb congestion enhances the synchronization of sympathetic outflow with muscle contraction.

In this report, we examined if the synchronization of muscle sympathetic nerve activity (MSNA) with muscle contraction is enhanced by limb congestion. To explore this relationship, we applied signal-averaging techniques to the MSNA signal obtained during short bouts of forearm contraction (2-s contraction/3-s rest cycle) at 40% maximal voluntary contraction for 5 min. We performed this analysis before and after forearm venous congestion; an intervention that augments the autonomic response to sustained static muscle contractions via a local effect on muscle afferents. There was an increased percentage of the MSNA noted during second 2 of the 5-s contraction/rest cycles. The percentage of total MSNA seen during this particular second increased from minute 1 to 5 of contraction and was increased further by limb congestion (control minute 1 = 25.6 +/- 2.0%, minute 5 = 32.8 +/- 2.2%; limb congestion minute 1 = 29.3 +/- 2.1%, minute 5 = 37.8 +/- 3.9%; exercise main effect <0.005; limb congestion main effect P = 0.054). These changes in the distribution of signal-averaged MSNA were seen despite the fact that the mean number of sympathetic discharges did not increase over baseline. We conclude that synchronization of contraction and MSNA is seen during short repetitive bouts of handgrip. The sensitizing effect of contraction time and limb congestion are apparently due to feedback from muscle afferents within the exercising muscle.

Adult↗

PubMed1993

Effects of maternal deprivation on the ACTH stress response in the infant rat.

Prolonged maternal deprivation during early ontogeny results in increased basal and stress-induced corticosterone levels. In the following experiments we examined whether these increases were due, at least in part, to augmented ACTH secretion. Thus, ACTH levels were measured in 24-hour maternally deprived and nondeprived 6-, 9-, and 12-day-old pups exposed to a mild stressor (i.e. saline injection followed by placement in a novel environment at room temperature). The results showed: (1) nondeprived pups showed a small response to saline--the response of deprived pups, however, was greater than that of nondeprived pups; (2) the magnitude of the response increased with age; (3) ACTH levels remained elevated for at least 30 min. Subsequent experiments examined whether the continuous exposure to novelty and/or loss of body heat could explain the persistence of this response. Neither variable affected the ACTH response to saline. Our results indicate that factors of maternal origin are partly responsible for the regulation of the ACTH response to stress. Furthermore, the persistence of the response suggests that the negative feedback system in the infant is immature.

Adrenocorticotropic Hormone↗

PubMed1976

Diagnosis of gastrinoma by the secretin suppression test.

In contrast to normal physiologic feedback suppression of serum gastrin by secretin, a paradoxic rise in the serum gastrin level has been observed in patients with gastrinoma after the administration of exogenous secretin. Exploitation of this phenomenon in the differential diagnosis of gastrinoma has been restricted by limited individual experience. Serial serum specimens for gastrin radioimmunoassay were collected from 13 patients with histologically proved gastrinoma both before and after the administration of Boot's secretin, 3 units per kilogram. Thirty-nine others with histologically proved gastrinoma who had been studied with exogenous secretin were identified in the literature. Both the peak gastrin and the integrated gastrin responses were increased after secretin administration in each of the patients in this combined series, although the magnitude of the increase was small in four patients. The absence of physiologic suppression by secretin implies neoplastic autonomy of gastrin releasing sites. While an augmented gastrin response to secretin is commonly seen in patients with gastrinoma, from a physiologic standpoint, a lack of suppression constitutes a positive secretin suppression test. Accumulated experience is consistent and suggests that this test is an important adjunt in the differential diagnosis of hypergastrinemia.

Gastrins↗

PubMed1987

Prostaglandin F2 alpha and oxytocin interactions in ovarian and uterine function.

The oxytocin-neurophysin gene is expressed in several nontraditional sites within the endocrine system. In the ovary its expression in the corpora lutea is initiated by ovulation. Ovarian oxytocin concentrations reach maximal levels around day 11 of luteal cycle and fall to a nadir at estrus. PGF2 alpha has the capacity to release oxytocin from the corpus luteum, and oxytocin in turn releases PGF2 alpha from the uterine endometrium or decidua. This positive feedback loop between the ovary and the uterus ensures the completion of luteolysis in species that depend on the presence of the uterus for the termination of luteal lifespan. Immunization against oxytocin has been shown to disrupt this loop, resulting in much-prolonged luteal cycles. In primates and other species in which luteal life span is independent of the uterus, an oxytocin PGF2 alpha interaction may take place within the ovary itself. At parturition a related interaction takes place which ensures the expulsion of the fetus and placenta in an orderly manner. Oxytocin of both pituitary and ovarian origin reaches the uterus via its blood supply and binds to two types of receptors: one on myometrial cells, the occupation of which initiates contractions, and the other on decidual cells, the occupation of which initiates prostaglandin generation. This prostaglandin diffuses into the adjacent myometrium and augments the oxytocin-induced contractions. In conjunction with a direct softening effect by prostaglandins on the cervix the augmented contractions achieve the force needed to dilate the cervix and expel the fetus. An additional source of oxytocin during labor may be the placenta, another non-traditional site for the occurrence of oxytocin.

Animals↗

PubMed1999

Fibrin fragment induction of plasminogen activator inhibitor transcription is mediated by activator protein-1 through a highly conserved element.

Plasminogen activator inhibitor type-1 (PAI-1), a serine protease inhibitor, affects the processes of fibrinolysis, wound healing, and vascular remodeling. We have demonstrated that PAI-1 transcription is induced by D dimer, a plasmin proteolytic fragment of fibrin, supporting its role in negative feedback on peri-cellular proteolysis. The focus of this study was to define the mechanism of D dimer's effects on PAI-1 transcription. D dimer increased the binding activity of the transcription factor activator protein-1 components c-fos/junD and c-fos mRNA levels in a time- and concentration-dependent manner to a greater extent than fibrinogen. Both basal and D dimer-induced PAI-1 transcriptional activity were entirely dependent on elements within the -161 to -48 bp region of the PAI-1 gene in fibroblasts. Mutations within the AP-1-like element (-59 to -52 bp) in the PAI-1 gene affected D dimer-induced transcriptional activity, c-fos/junD DNA binding, and basal and c-fos inducible PAI-1 transcriptional activity. Furthermore, expression of either wild-type or mutant c-fos proteins augmented or diminished the response of the PAI-1 promoter (-161 to +26 bp) to D dimer, respectively. D dimer-induced binding of c-fos/junD to the highly conserved and unique AP-1 like element in the PAI-1 gene provides a mechanism whereby specific fibrin fragments control fibrin persistence at sites of inflammation, fibrosis, and neoplasia.

Animals↗

PubMed1993

Augmented ACTH responses to stress in adrenalectomized rats replaced with constant, physiological levels of corticosterone are partially normalized by acute increases in corticosterone.

Adrenalectomized rats replaced with constant, physiological levels of corticosterone via a subcutaneous pellet (Pellet) have normal basal morning ACTH but exhibit enhanced and prolonged ACTH responses to stress vs. sham-operated (Sham) rats. It has not been determined if the lack of either stress-induced or circadian increases in corticosterone, both of which are missing in Pellet rats, may account for this enhanced response. To test the extent to which stress-associated increases in corticosterone alone can normalize stress-induced hypersecretion of ACTH, we approximated endogenous secretion by injecting additional corticosterone in Pellet rats via an indwelling subcutaneous cannula, 5 min before hypoxia stress (10% O2). A corticosterone dose of 666 micrograms/kg (Pellet+B), but not 333 micrograms/kg (Pellet+Low B), produced plasma corticosterone levels comparable to those in Shams and normalized stress-induced but not post-stress plasma ACTH. Administration of the type II corticosteroid receptor antagonist RU 38486 30 min before corticosterone reversed this inhibition. We conclude that enhanced ACTH responses to stress in Pellet rats result in large part from lack of type II receptor-mediated feedback inhibition by corticosterone increases during stress, although prior circadian increases in corticosterone may also be required.

Adrenalectomy↗

PubMed2003

Estradiol supplementation enhances submaximal feed-forward drive of growth hormone (GH) secretion by recombinant human GH-releasing hormone-1,44-amide in a putatively somatostatin-withdrawn milieu.

To test the clinical hypothesis that an estrogen-enriched milieu enhances GHRH action, we administered placebo (Pl) and estradiol-17 beta (E(2)) orally for 23 d to six postmenopausal women in a prospectively randomized, double-masked, within-subject crossover design with 6 wk intervening. The GHRH stimulation protocol entailed consecutive i.v. infusion of L-arginine and a single i.v. pulse of saline or one of five randomly ordered doses of recombinant human GHRH-1,44-amide (0.03, 0.1, 0.3, 1.0, or 3.0 microg/kg) in a total of 12 separate morning, fasting sessions. GH secretion was monitored by sampling blood every 10 min for 6 h; chemiluminescence assay of GH concentrations; deconvolution analysis of stimulated GH release; and nonlinear dose-response reconstruction. Supplementation with E(2), compared with Pl: 1) increased (mean +/- SEM) E(2) concentrations from 18 +/- 3 (Pl) to 164 +/- 12 pg/ml (to convert to picomoles per liter, multiply by 3.57) (P < 0.001); 2) decreased IGF-I concentrations from 181 +/- 14 to 120 +/- 11 microg/liter (P < 0.01); 3) elevated mean GH concentrations from 0.27 +/- 0.06 to 0.59 +/- 0.08 microg/liter (P = 0.014); 4) potentiated GH secretion stimulated by L-arginine alone by 1.43-fold (P = 0.012); 5) reduced the ED(50) of GHRH from 0.27 +/- 0.02 to 0.13 +/- 0.01 microg/kg (P < 0.01), denoting enhanced GHRH potency; and 6) heightened the maximal slope of the dose-response function from 1.1 +/- 0.1 to 1.4 +/- 0.05 [( microg/liter) ( microg/kg)(-1)] (P < 0.05), signifying augmented pituitary sensitivity. The foregoing facilitative mechanisms were specific because E(2) replacement did alter maximal L-arginine/GHRH-induced GH secretion, indicating unchanged secretagogue efficacy. In conclusion, inasmuch as E(2) also attenuates inhibition of GH secretion by infused somatostatin and potentiates stimulation of GH secretion by GH-releasing peptide-2, we postulate that estrogenic steroids drive pulsatile GH production in part via mechanisms that include all three of GHRH, somatostatin, and putatively GH-releasing peptide/ghrelin signaling.

Aged↗