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PubMed1998

Gamma-linolenic acid does not augment long-chain polyunsaturated fatty acid omega-3 status.

Augmentation of long chain polyunsaturated omega3 fatty acid (LCPUFA omega3) status can be reached by consumption of fish oil or by improvement of the conversion of alpha-linolenic acid (ALA) to LCPUFA omega3. Since gamma-linolenic acid (GLA) might activate the rate-limiting delta-6 desaturation, we investigated whether GLA augments LCPUFA omega3 status. Eight adults received 1.4 g GLA for 4 weeks and subsequently 2.2 g ALA+1.4 g GLA daily during another 4 weeks. Another seven adults received a daily oral dose of 2.2 g ALA for 4 weeks, and subsequently 2.2 g ALA+1.4 g GLA during another 4 weeks. ALA, or ALA+GLA, did not significantly augment EPA and DHA contents. We conclude that the LCPUFA omega3 status can not be improved by supplementation of low dose GLA, neither by co-supplementation of ALA. Poor conversion of ALA to LCPUFA omega3 may be caused by preferential beta-oxidation of ALA, negative feedback of arachidonic acid from the omnivorous diet, or by the low dietary ALA/LA ratio.

Adult↗

PubMed2001

Preexposure of murine macrophages to CpG oligonucleotide results in a biphasic tumor necrosis factor alpha response to subsequent lipopolysaccharide challenge.

Bacterial DNA and synthetic oligonucleotides containing CpG sequences (CpG-DNA and CpG-ODN) provoke a proinflammatory cytokine response (tumor necrosis factor alpha [TNF-alpha], interleukin-12 [IL-12], and IL-6) and increased mortality in lipopolysaccharide (LPS)-challenged mice via a TNF-alpha-mediated mechanism. It was hypothesized that preexposure of macrophages to CpG-ODN would result in an increased TNF-alpha response to subsequent LPS challenge in vitro. Using the murine macrophage cell line RAW 264.7, we demonstrated both a rapid proinflammatory cytokine response (TNF-alpha) and a delayed inhibitory cytokine response (IL-10) with CpG-ODN. Preexposure of macrophages to CpG-ODN for brief periods (1 to 3 h) augmented TNF-alpha secretion and mRNA accumulation following subsequent LPS challenge (1 microg/ml). However, prolonged preexposure to CpG-ODN (6 to 9 h) resulted in suppression of the TNF-alpha protein and mRNA response to LPS. The addition of anti-IL-10 antibody to CpG-ODN during preexposure resulted in an increase in the LPS-induced TNF-alpha response over that induced by CpG-ODN preexposure alone. Thus, while brief preexposure of macrophages to CpG-ODN augments the proinflammatory cytokine response to subsequent LPS challenge, prolonged preexposure elicits IL-10 production, which inhibits the TNF-alpha response. Although the initial proinflammatory effects of CpG-DNA are well established, the immune response to CpG-DNA may also include autocrine or paracrine feedback mechanisms, leading to a complex interaction of proinflammatory and inhibitory cytokines.

Animals↗

PubMed2005

Tracing from fat tissue, liver, and pancreas: a neuroanatomical framework for the role of the brain in type 2 diabetes.

The hypothalamus uses hormones and the autonomic nervous system to balance energy fluxes in the body. Here we show that the autonomic nervous system has a distinct organization in different body compartments. The same neurons control intraabdominal organs (intraabdominal fat, liver, and pancreas), whereas sc adipose tissue located outside the abdominal compartment receives input from another set of autonomic neurons. This differentiation persists up to preautonomic neurons in the hypothalamus, including the biological clock, that have a distinct organization depending on the body compartment they command. Moreover, we demonstrate a neuronal feedback from adipose tissue that reaches the brainstem. We propose that this compartment-specific organization offers a neuroanatomical perspective for the regional malfunction of organs in type 2 diabetes, where increased insulin secretion by the pancreas and disturbed glucose metabolism in the liver coincide with an augmented metabolic activity of visceral compared with sc adipose tissue.

Adipose Tissue↗

PubMed1994

Androgen-receptor blockade enhances pulsatile luteinizing hormone production in late pubertal males: evidence for a hypothalamic site of physiologic androgen feedback action.

To determine potential mechanisms by which androgens alter gonadotropin secretion and elimination in the pubertal male, we administered the potent nonsteroidal androgen receptor blocking agent, flutamide, to eight males with Tanner IV or V genital development. Venous blood samples were obtained every 10 min for 24 h and assayed for LH by a sensitive and high-precision fluorimmunoassay. Subjects were studied before and after the administration of flutamide. Deconvolution analysis was used to assess specific pulsatile LH secretory characteristics and estimate LH production and metabolic clearance rates quantitatively. After antagonism of endogenous androgen action, mean 24-h serum LH concentrations increased significantly. An increased mean 24-h LH production rate, without evident changes in serum LH half-life, accounted for the increase in average serum LH levels. The increased daily secretion rate of LH was in turn due to both an augmented mass of LH released per secretory episode and increased frequency of secretory events. There was no demonstrable change in the maximal rate of LH secretion attained within each secretory event. Serum concentrations of total testosterone, free-testosterone, and 17 beta-estradiol all increased during blockade of androgen action. Administration of the antiandrogen had no measurable effect on the pituitary response to a single maximally effective dose of exogenous gonadotropin releasing hormone (GnRH). These results indicate that, in the late pubertal male, endogenous androgen exerts negative feedback control of gonadotropin secretion primarily at a hypothalamic site reflected by regulation of the frequency of pulsatile LH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1988

Opiate-induced hypersensitivity to testosterone feedback: pituitary involvement.

We have examined the mode of morphine's (M) action to increase the sensitivity of castrated male rats to the inhibitory feedback action of testosterone (T) on LH release. In castrated rats, sc implantation of M pellets or 5-mm long T-filled capsules (T5) failed to suppress LH release, but a combination of M and T5 drastically decreased serum LH levels. Likewise, while treatment with a higher dose of T (30-mm long implant, sc) suppressed LH release, combined treatment with M and T30 produced a further suppression of LH levels. We have now assessed the in vitro release rate of LHRH from the medial basal hypothalamus-preoptic area of castrated rats treated with M and/or T as well as the in vivo pituitary LH response to LHRH challenge in similarly treated rats. Interestingly, the in vitro basal and naloxone-induced LHRH release from the medial basal hypothalamus-preoptic area of the six groups of rats was similar, regardless of whether LH levels were in the high castrate or low basal range. On the other hand, M treatment greatly attenuated LH release in vivo in response to LHRH challenge (10pmol-1pmol) [corrected] in T-treated rats. In fact, LH increments in response to 1pmol [corrected] LHRH, seen in control, T5, and T30 groups, were abolished by additional M treatment of T-treated rats. This in vitro assessment of LHRH release suggests that the drastic decrease in LH release in T-plus M-treated rats may not be due to impaired LHRH release, but, rather, be due in part to reduced pituitary responsiveness to intermittent endogenous LHRH signals. The reduced pituitary responsiveness to LHRH in T-plus M-treated rats may be a consequence of either a direct pituitary effect of opiates in conjunction with T or augmented action of hypothalamic neurohumoral agents which may inhibit LH release on their own or antagonize the LH-releasing action of LHRH at the level of pituitary gonadotrophs.

Animals↗

PubMed1995

Amplitude and frequency modulation of pulsatile luteinizing hormone-releasing hormone release.

1. A variety of neuroendocrine approaches has been used to characterize cellular mechanisms governing luteinizing hormone-releasing hormone (LHRH) pulse generation. We review recent in vivo microdialysis, in vitro superfusion, and in situ hybridization experiments in which we tested the hypothesis that the amplitude and frequency of LHRH pulses are subject to independent regulation via distinct and identifiable cellular pathways. 2. Augmentation of LHRH pulse amplitude is proposed as a central feature of preovulatory LHRH surges. Three mechanisms are described which may contribute to this increase in LHRH pulse amplitude: (a) increased LHRH gene expression, (b) augmentation of facilitatory neurotransmission, and (c) increased responsiveness of LHRH neurons to afferent synaptic signals. Neuropeptide Y (NPY) is examined as a prototypical afferent transmitter regulating the generation of LHRH surges through the latter two mechanisms. 3. Retardation of LHRH pulse generator frequency is postulated to mediate negative feedback actions of gonadal hormones. Evidence supporting this hypothesis is reviewed, including results of in vivo monitoring experiments in which LHRH pulse frequency, but not amplitude, is shown to be increased following castration. A role for noradrenergic neurons as intervening targets of gonadal hormone negative feedback actions is discussed. 4. Future directions for study of the LHRH pulse generator are suggested.

Animals↗

PubMed1992

The role of the endothelial cell in leukotriene biosynthesis.

Endothelial cells do not contain 5-lipoxygenase and thus are unable to generate LTA4 from arachidonate. Nonetheless, endothelial cells may play an important role in leukotriene synthesis by virtue of their ability to metabolize LTA4 derived from activated polymorphonuclear leukocytes (PMNL) and to modulate PMNL 5-lipoxygenase activity. Porcine aortic endothelial cells were found to metabolize exogenous LTA4 to LTC4, and under some conditions human umbilical vein endothelial cells have been found to generate LTB4. Production of LTB4 by these cells appears to be under poorly understood cellular control, and it remains a controversial area of research. Under physiologic conditions, endothelial cells are in constant contact with circulating PMNL, which are known to generate substantial amounts of LTA4. When these two cell types are coincubated in vitro, clear evidence of transcellular metabolism of PMNL-derived LTA4 to LTC4 by endothelial cells is found. Coincubations produce from two to greater than 10 times more LTC4 than either cell alone. In contrast to these findings, when these cells were activated by the receptor-mediated agonist fMLP, evidence for an endothelial cell inhibition of PMNL 5-lipoxygenase was obtained. Rather than augmentation of LTC4 production, as seen with A23187 activation, coincubation activated by fMLP generated significantly less LTC4 (0.23 +/- 0.08 versus 0.75 +/- 0.39 pmol/10(7) cells). The endothelial cell inhibition was removed when these cells were pretreated with aspirin, suggesting that their major cyclooxygenase product, prostacyclin, acts as a feedback regulator of LT synthesis. When cyclooxygenase was blocked, significant transcellular LTC4 synthesis was once again apparent (1.66 +/- 0.44 pmol/10(7) cells).

Animals↗

PubMed2004

TCR- and CD28-mediated recruitment of phosphodiesterase 4 to lipid rafts potentiates TCR signaling.

Ligation of the TCR along with the coreceptor CD28 is necessary to elicit T cell activation in vivo, whereas TCR triggering alone does not allow a full T cell response. Upon T cell activation of human peripheral blood T cells, we found that the majority of cAMP was generated in T cell lipid rafts followed by activation of protein kinase A. However, upon TCR and CD28 coligation, beta-arrestin in complex with cAMP-specific phosphodiesterase 4 (PDE4) was recruited to lipid rafts which down-regulated cAMP levels. Whereas inhibition of protein kinase A increased TCR-induced immune responses, inhibition of PDE4 blunted T cell cytokine production. Conversely, overexpression of either PDE4 or beta-arrestin augmented TCR/CD28-stimulated cytokine production. We show here for the first time that the T cell immune response is potentiated by TCR/CD28-mediated recruitment of PDE4 to lipid rafts, which counteracts the local, TCR-induced production of cAMP. The specific recruitment of PDE4 thus serves to abrogate the negative feedback by cAMP which is elicited in the absence of a coreceptor stimulus.

1-Methyl-3-isobutylxanthine↗

PubMed1997

Reciprocal relation between VEGF and NO in the regulation of endothelial integrity.

Balloon angioplasty disrupts the protective endothelial lining of the arterial wall, rendering arteries susceptible to thrombosis and intimal thickening. We show here that vascular endothelial growth factor (VEGF), an endothelial cell mitogen, is upregulated in medial smooth muscle cells of the arterial wall in response to balloon injury. Both protein kinase C (PKC) and tyrosine kinase pp60src mediate augmented VEGF expression. In contrast, nitric oxide (NO) donors inhibit PKC-induced VEGF upregulation by interfering with binding of the transcription factor activator protein-1 (AP-1) to the VEGF promoter. Inhibition of VEGF promoter activation suggests that NO secreted by a restored endothelium functions as the negative feedback mechanism that downregulates VEGF expression to basal levels. Administration of a neutralizing VEGF antibody impaired reendothelialization following balloon injury performed in vivo. These findings establish a reciprocal relation between VEGF and NO in the endogenous regulation of endothelial integrity following arterial injury.

Animals↗

PubMed2005

Long-term cortical plasticity evoked by electric stimulation and acetylcholine applied to the auditory cortex.

Auditory fear conditioning with tone bursts followed by electric leg stimulation activates neurons not only in the auditory and somatosensory systems but also in many other regions of the brain and elicits shifts in the best frequencies (BFs) of collicular and cortical neurons, i.e., reorganization of the frequency (co-chleotopic) maps in the inferior colliculus and auditory cortex (AC). What are the neural elements minimally necessary for evoking long-term cortical BF shifts? We found that: (i) both electric stimulation and acetylcholine applied to the AC evoke the long-term cortical BF shift as does the conditioning; (ii) both electric stimulation of the AC and acetylcholine applied to the inferior colliculus increase the short-term collicular BF shift evoked by the cortical electric stimulation but do not change it into long-term; and (iii) as this short-term collicular BF shift is blocked by atropine, the development of the long-term cortical BF shift becomes slow and small. Therefore, the most essential neural elements for evoking the long-term cortical BF shift are the AC, corticofugal feedback and the cholinergic nucleus. Our current data support the Gao-Suga model, which hypothesizes that the small short-term cortical BF shifts are evoked by tonal stimuli without the association of conditioned and unconditioned stimuli in the multisensory thalamic nuclei and that these BF shifts are augmented and changed into the large long-term BF shifts by cholinergic neurons.

Acetylcholine↗

PubMed1974

Frequency characteristics of retinal neurons in the carp.

Frequency characteristics of various retinal neurons in the carp were studied using sinusoidally modulated light as an input. They were affected by both intensity and pattern of illumination. In the horizontal cells, in which the effect of light intensity was studied most extensively, an increase in the light intensity brought about a decrease of the gain, which was more marked at lower frequencies, resulting in a shift of cutoff frequency towards higher frequencies and in a slight low frequency attenuation. A decrease in the area illuminated had an effect similar to a decrease in the light intensity. In the receptor, the low frequency attenuation was not apparent even at high light intensities. The adaptation process in receptors was not sufficient to explain the low frequency attenuation in the horizontal cells, and a possible contribution of negative feedback from horizontal cells to receptors was suggested. In the bipolar cell, the lateral interaction played an important role. An increase in an area resulted in the suppression of the response at low frequencies where the phases of the center and the surround responses were opposed, but in the augmentation near 5 Hz where the two responses were in phase. In amacrine cells, a low frequency attenuation and a phase advance at low frequencies were very prominent, and were considered to be due mainly to a process designated here as the neural adaptation.

Adaptation, Ocular↗

PubMed2002

Activation of mitogen-activated protein kinases during granulocyte apoptosis in patients with severe sepsis.

Reduction of neutrophil apoptosis represents a major cause for granulocytosis and increases the destructive potential of theses cells during systemic inflammatory response syndrome (SIRS) and sepsis. In this light, the role of protein kinases for the regulation of altered neutrophil apoptosis under infectious conditions was investigated. Neutrophils, obtained from patients with severe sepsis (n = 18), were incubated ex vivowith either LPS (1 microg/mL) or interferon-gamma (IFN-gamma; 10 ng/mL) for 16 h. Apoptosis was determined by propidium iodine (PI) staining of DNA fragments and was compared with the rate of spontaneous apoptosis. Tyrosine kinases were inhibited by herbimycin (1 microM), the mitogen-activated protein (MAP) kinase ERK was inhibited with PD98059 (50 microM), and p38 MAP kinase was inhibited with SB203580 (5 microM). Herbimycin reconstituted LPS-reduced apoptosis in neutrophils from controls (39.9 +/- 3.8%) and patients (20.8 +/- 2.8%) to levels seen in spontaneous apoptosis (70.9 +/- 2.8% and 40.7 +/- 3.7%, respectively). Inhibition of the ERK kinase yielded similar results, whereas SB203580 had no effect on LPS-reduced apoptosis. However, inhibition of p38 partially reconstituted IFN-gamma-reduced apoptosis (51.3 +/- 7.7% and 25.6 +/- 5.8%) and increased spontaneous apoptosis (82.4 +/- 3.3% and 42.0 +/- 5.8%) in controls and patients, respectively. Western blot analysis revealed phosphorylation of both MAP kinases by LPS, but not by IFN-gamma. Inhibition of MAP kinases did not augment neutrophil apoptosis in patients to the level seen in controls, indicating that other mechanisms must be involved in the regulation of neutrophil apoptosis. Although the ERK kinase regulates LPS-induced reduction of apoptosis, the p38 MAP kinase might be involved in IFN-gamma signaling and the feedback regulation of neutrophil apoptosis.

Adolescent↗

PubMed2006

Passive ventricular constraint prevents transmural shear strain progression in left ventricle remodeling.

BACKGROUND: Passive ventricular constraint provides external cardiac support to reduce left ventricular (LV) wall stress and myocardial stretch, which are primary determinants of LV remodeling. Altered wall strain results in cytokine and reactive oxygen species production, which, in turn, stimulates apoptosis and extracellular matrix disruption and could be an important trigger for adverse global LV dilatation and remodeling. The effects of the Acorn cardiac support device (CSD) on regional transmural LV wall strains, however, remain unknown. METHODS AND RESULTS: Thirty-three sheep had transmural radiopaque beadsets surgically inserted into the anterior basal and lateral equatorial LV walls, with additional markers silhouetting the left ventricle. Eight animals had CSD implanted (myocardial infarction [MI]+CSD). One week thereafter, the MI+CSD group and 10 animals without CSD (MI) underwent posterior LV infarction by snaring obtuse marginal coronary arteries. Fifteen animals (Sham) had no infarction or CSD. 4D marker dynamics were measured with biplane videofluoroscopy 1 and 8 weeks postoperatively. LV volumes, sphericity index, and transmural circumferential, longitudinal, and radial systolic strains were analyzed. Compared with Sham, infarction (MI) dilated the heart, reduced sphericity index (LV length/width), and increased longitudinal-radial shear strains in the inner half of both the anterior and lateral LV walls. CSD prevented this shear strain perturbation, minimized LV end diastolic volume increase, and augmented the LV sphericity index. CONCLUSIONS: Prophylactic CSD prevented infarct-induced shear strain progression not only in myocardium adjacent to, but also remote from, the infarct. CSD also prevented LV dilatation and sphericalization. By attenuating shear strain abnormalities, CSD could prevent the heart from entering into a positive feedback loop of further LV dilatation and exaggeration of LV wall stress and may reduce biochemical triggers portending adverse LV remodeling.

Animals↗

PubMed1996

The production of macrophage inflammatory protein-1 alpha by human basophils.

Macrophage inflammatory protein-1alpha (MIP-1alpha) has previously been shown to be produced by mononuclear cells, eosinophils, and neutrophils. Its production by basophils has not been investigated. The objective of this study was to investigate the production of MIP-1alpha by basophils. Peripheral blood basophils were separated by Percoll gradient centrifugation, cultured overnight, and processed for double immunocytochemistry using Abs against MIP-1alpha and FcepsilonRIalpha (alpha subunit of IgE receptor type 1). We demonstrated that basophils expressed immunoreactive MIP-1alpha upon stimulation with anti-IgE. Less than 5% of the basophils stained for MIP-1alpha without stimulation. The secretion of MIP-1alpha by basophils was studied by ELISA. In these experiments, basophils were further enriched to 65 to 99% (median, 86%) by a negative selection method. Basophils released MIP-1alpha when stimulated by Abs against IgE and FCepsilonRIalpha as well as IL-3 and the calcium ionophore, A23187. In parallel experiments, PBMC, eosinophils, and neutrophils did not produce MIP-1alpha in response to anti-IgE, but they did so in response to A23187. No MIP-1alpha release was detected in platelet preparations. Preincubation with IL-3 (15 min or 18 h) augmented anti-IgE-included basophil MIP-1alpha production. The secretion of MIP-1alpha by basophils was detectable shortly after stimulation and gradually increased over 24 h. Since MIP-1alpha has potent inflammatory and histamine-releasing activities, its production by basophils may indicate a positive feedback mechanism for allergic inflammation.

Antibodies, Anti-Idiotypic↗

PubMed1984

Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man.

We have tested the participation of endogenous opiate pathways in the negative feedback actions of gonadal steroids on pulsatile properties of luteinizing (LH) hormone release in normal men. To this end, sex steroid hormones were infused intravenously at dosages that under steady state conditions selectively suppressed either the frequency or the amplitude of the pulsatile LH signal. The properties of pulsatile LH secretion were assessed quantitatively by computerized analysis of LH series derived from serial blood sampling over 12 h of observation. When the pure (nonaromatizable) androgen, 5-alpha-dihydrotestosterone, was infused continuously for 108 h at the blood production rate of testosterone, we were able to achieve selective inhibition of LH pulse frequency akin to that observed in experimental animals after low-dosage androgen replacement. Under these conditions, serum concentrations of testosterone and estradiol-17 beta did not change significantly, but serum 5 alpha-dihydrotestosterone concentrations increased approximately two- to threefold, with a corresponding increase in levels of its major metabolite, 5 alpha-androstan-3 alpha, 17 beta-diol. In separate experiments, the infusion of estradiol-17 beta at its blood production rate over a 4.5-d interval selectively suppressed LH pulse amplitude without influencing LH pulse frequency. Estrogen infusion increased serum estradiol-17 beta levels approximately twofold without significantly altering blood androgen concentrations. We then used these schedules of selective androgen or estrogen infusion to investigate the participation of endogenous opiates in the individual inhibitory feedback actions of pure androgen or estrogen on pulsatile LH release by administering a potent and specific opiate-receptor antagonist, naltrexone, during the infusions. Our observations indicate that, despite the continuous infusion of a dosage of 5 alpha-dihydrotestosterone that significantly suppresses LH pulse frequency, co-administration of an opiate-receptor antagonist effectively reinstates LH pulse frequency to control levels. Moreover, during the infusion of a suppressive dose of estradiol-17 beta, opiate receptor blockade significantly augments LH pulse frequency and increases LH peak amplitude to control levels. Thus, the present studies in normal men demonstrate for the first time that the selective inhibitory action of a pure androgen on LH pulse frequency is effectively antagonized by opiate-receptor blockade. This pivotal observation indicates that opiatergic and androgen-dependent mechanisms specifically and coordinately control the hypothalamic pulse generator for gonadotropin-releasing hormone (GnRH)

Adult↗

PubMed2006

The impact of affect and frequency on lexical decision: the role of the amygdala and inferior frontal cortex.

The current study used event-related fMRI to examine BOLD responses associated with two factors that behaviorally determine speed of lexical decision: frequency and emotion. Thirteen healthy adults performed a visual lexical decision task, discriminating between words and orthographically and phonologically legal nonwords. The study involved a 2 (Frequency: high and low) x 3 (Emotional arousal: highly negative, mildly negative, and neutral words) design with word categories matched for number of letters and concreteness. There were significant main effects for both frequency and emotion in lexical decision reaction times but no significant interaction. Negative word lexical decisions were associated with increased activation in bilateral amygdala and middle temporal cortex as well as rostral anterior and posterior cingulate cortex. Low-frequency word lexical decisions, relative to high-frequency word lexical decisions, were associated with increased bilateral activity in inferior frontal cortex. Inferior frontal cortex activation was particularly low during lexical decision for high-frequency emotional words but significant for high-frequency neutral emotional words. We suggest that this is because the semantic representation of high-frequency emotional words may receive sufficient additional augmentation via the reciprocal activation from the amygdala such that selective augmentation by inferior frontal cortex to achieve lexical decision is unnecessary.

Adult↗

PubMed1993

Genetic complementation reveals a novel regulatory role for 3' untranslated regions in growth and differentiation.

Differentiated skeletal muscle cells cease dividing and sustain expression of a battery of tissue-specific genes. To identify regulators of growth and differentiation, we used a genetic complementation approach. Following introduction of a cDNA expression library into a differentiation-defective myoblast mutant (NMU2), cDNAs were isolated that activated muscle-specific promoters. The complementing cDNAs were identified as muscle structural genes, troponin I, tropomyosin, and alpha-cardiac actin, and their activity was mapped to the 3' untranslated region (3'UTR). The 3'UTRs augmented the differentiation of wild-type muscle cells. Upon expression in 10T1/2 fibroblasts, proliferation was suppressed, indicating that the effects of the 3'UTRs are not limited to myogenic cells. These data suggest that 3'UTRs of certain differentiation-specific RNAs are trans-acting regulators in a feedback loop that inhibits cell division and promotes differentiation.

Actins↗

PubMed1986

Intradermal administration of 4-hydroperoxy-cyclophosphamide during contact sensitization potentiates effector T cell responsiveness in draining lymph nodes.

4-Hydroperoxy-cyclophosphamide (4-HPCY) is an in vitro active form of cyclophosphamide. In a previous study, using an in vivo contact sensitivity model in the guinea pig, we demonstrated that intradermal injection of small amounts (50-200 micrograms) of 4-HPCY at the sensitization site resulted in strong potentiation of contact hypersensitivity (Boerrigter and Scheper, 1984). It was postulated that 4-HPCY induces a local decrease of feedback control within the draining antigenically stimulated lymph nodes. The present data are in support of this view: Lymph node hyperplasia induced by contact sensitization (to dinitrochlorobenzene or oxazolone) was further enhanced by 4-HPCY treatment. The paracortical area was preferentially enlarged. 4-HPCY-treated lymph nodes showed an augmentation of hapten-specific T effector cell function as determined in transfer experiments. The response of such lymph node-derived cells to the T cell mitogen PHA was enhanced. Although 4-HPCY treatment resulted simultaneously in a decrease in responsiveness of draining lymph node-derived cells to the B cell mitogen lipopolysaccharide, anti-hapten antibody production was not affected. The present study demonstrates that important similarities exist between the effects of local 4-HPCY treatment and systemic cyclophosphamide pretreatment on the immune response. As systemic treatment with a high dose of cyclophosphamide is known to have serious side effects, the present local protocol provides a new attractive and versatile strategy for T cell immunopotentiation.

Animals↗