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PubMedDate not supplied

Isolation of human myeloid dendritic cells from tumor tissue and peripheral blood.

BACKGROUND: Human myeloid dendritic cells (MDC) have been identified in human solid tumor tissue of head and neck squamous cell carcinoma (HNSCC), their cellular functions being strongly affected in this environment. The characterization of MDC differentiation and functions requires the establishment of highly efficient isolation procedures. MATERIALS AND METHODS: Human MDC were isolated from peripheral blood and solid HNSCC using density gradient centrifugation or preparation of single cell suspensions, respectively. The cells were isolated by "magnetic bead separation" using magnetically-labelled antibodies and were analyzed by flow cytometry. RESULTS: The isolation of human MDC from peripheral blood or solid HNSCC tissue resulted in highly enriched cell populations and revealed cell purities of about 90%. CONCLUSION: The scale of molecular investigations on human myeloid dendritic cells is restricted by the limited proportion of this cell type. Thus, highly efficient and gentle MDC isolation procedures are essential to characterize in vivo matured MDC.

Adolescent↗
PubMed1999

Arachidonic acid metabolism in nasal tissue and peripheral blood cells in aspirin intolerant asthmatics.

Aspirin intolerance (AI) is characterized by polypous rhinosinusitis, bronchial asthma and adverse reactions to aspirin. The common intolerance to all cyclo-oxygenase inhibitors allows us to focus study of the pathogenesis of AI on the metabolism of arachidonic acid (AA). We studied the metabolism of AA in nine aspirin intolerant asthmatics (AIA) and eight healthy volunteers (controls) by measuring prostaglandin E2 (PGE2) and peptido-leukotrienes (pLT = LTC4/D4/E4) in nasal tissue and peripheral blood cells (PBCs) using a specific immunoassay. In all patients with AI the tests were performed before and after bronchial provocation with lysine-ASA. In the control group the tests were done before and after 500 mg ASA p.o. The release of pLT in nasal polyps of AIA was found to be significantly higher than in normal mucosa of AIAs and controls. In every tissue a significant increase of pLT after aspirin challenge was observed. Nasal polyps of AIA show a significantly lower release of PGE2 than normal mucosa of AIAs and controls. Peripheral blood cells of AIA show a significantly higher release of pLT and a significantly lower release of PGE2 than PBCs of controls. Therefore clinical manifestations of AI may be based on an alteration of AA metabolism in AIA.

Adult↗
PubMed1991

Regional expression of transforming growth factor-alpha mRNA in the rat central nervous system.

The expression of transforming growth factor-alpha (TGF alpha) mRNA in various regions of the adult rat central nervous system (CNS), as well as in selected peripheral tissues was examined using Northern blot analysis. The highest expression was also found in the cerebral spinal cord, with the levels of TGF alpha mRNA being 5- to 6-fold higher in this tissue than in any other examined. Significant expression was also found in the olfactory bulb, anterior olfactory nucleus, corpus striatum, hippocampus, ventral mesencephalon and caudal brainstem. Of the peripheral tissues examined, only adrenal gland expressed TGF alpha mRNA at similar levels. Lower, but detectable, expression was found in prefrontal cortex, cerebral cortex and cerebellum. The latter levels were similar to those observed in lung, liver, kidney and, variable, salivary gland. These data demonstrate a widespread but differential distribution of TGF alpha mRNA throughout the rat CNS, and indicate relatively high levels of expression of this growth factor in central versus peripheral tissues.

Animals↗
PubMedDate not supplied

[Inhibition of pancreatic beta-cell secretion during "glucose clamp" in patients with polycystic ovary syndrome].

Insulin-resistance is a well-known feature of polycystic ovary syndrome (PCOS) and the present paper investigates the comparative roles of the peripheral tissues and the pancreatic beta-cells in its pathogenesis. The study was conducted on 5 young women with PCOS, all of normal weight and glucose tolerance in whom the glucose-insulin clamp test had revealed reduced peripheral glucose uptake that was not influenced by other conditions typically associated with insulin-resistance. Beta-cell function was investigated in these patients and 5 healthy controls via the assessment of the efficiency of the insulin/insulin feedback which involved studying the suppression of plasma C peptide during the glucose clamp. The results suggested that the insulin/insulin beta-cell feedback mechanism had retained its efficiency despite proven peripheral insulin-resistance. These data do not therefore support the hypothesis advanced by others that there is some sort of beta-cell insulin resistance parallel to the insulin resistance of the peripheral tissues. On the basis of those results it is rather believed that in PCOS the insulin-resistance is generated peripherally while the insulin/insulin feedback in the beta-cell is unimpaired. This obliges us to rethink the role of the hyperinsulinism encountered in PCOS and suggests that the changed sensitivity of the peripheral tissues to insulin activity may constitute a primary event in the genesis of insulin-resistance. This type of behavior has been demonstrated in the obese and in people with acanthosis nigricans, all with normal glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2003

[Dynamics of local oxygen consumption an extraction under the condition of altered oxygen turnover in humans during head-down bed rest].

Invasive and non-invasive measurements were used to evaluate methods of correcting oxygen consumption and extraction within the local circulation in bedrested human subjects. For the first time demonstrated was the vanity of attempts to improve O2 supply to the human peripheral tissues by re-establishment of the circulating blood volume and increasing oxygen content in the affluent blood. The reason can be that HD bed rest impacts the ability of peripheral tissues to augment consumption of the surplus oxygen. The experiment showed that preliminary infusion of an antihypoxant (gamma-hydroxibutyric acid) recovers this ability even in case of abundant oxygen. Based on results of the investigation, oxygen supply correction can be considered as a way to improve (when necessary) oxygen supply to the human peripheral tissues during HD bed rest.

Adult↗
PubMed1990

Distribution of MHC class II antigens in feline tissues and peripheral blood.

A new monoclonal antibody raised against gradient-purified feline immunodeficiency virus was found to recognize a bimolecular complex, comprising 27-29 kD and 32-35 kD subunits, on feline peripheral blood lymphocytes. Immunoperoxidase staining of feline tissues with this antibody, designated 43.2H2, demonstrated a reactivity pattern similar to that described for MHC II antigens of the dog, horse, and pig, but differed from human and mouse in having staining of T-cell zones in spleen and lymph nodes. Flow cytometric analysis revealed that 42.3H2 reacted with 88.97% +/- 16.00% of feline peripheral blood lymphocytes (n = 20). This high level of reactivity was found to be consistent by repeated sampling over a 4-month period. Two-color flow cytometric analysis was used to determined the reactivity pattern on lymphocyte subsets: 88.92% +/- 7.30% of CD4+ lymphocytes were 42.3H2-positive, while 85.99% +/- 11.46% of CD8+ cells were positive (n = 11 for both). B lymphocytes had the highest reactivity (99.47% +/- 0.45; n = 9) and also had the highest fluorescence intensity. By gating based on light scatter properties, 95.06% +/- 7.35% of monocytes were 42.3H2-reactive (n = 18), while granulocytes were negative.

Animals↗
PubMed1996

Subcutaneous tissue oxygen pressure: a reliable index of peripheral perfusion in humans after injury.

The usual initial life-threatening effect of injury is hypovolemic shock. In the hierarchical physiologic response to hypovolemia, perfusion of peripheral tissues is sacrificed early and restored late. But the usual hemodynamic and metabolic measurements of blood pressure, urine output, and base deficit are not reliable indices of peripheral perfusion. Although the Clark electrode can quantitate tissue oxygen pressure and thereby serve as an index of perfusion, its use is compromised by several technical deficiencies. Recently, an optical method (optode) using fluorescent technology has been developed for measurement of oxygen tension in subcutaneous tissue (P sgO2). Our studies compared this device with the Clark electrode in the laboratory and tested its value in both animal and clinical studies of hypovolemic shock. The results of these several studies demonstrated that: (1) the new oximeter tracked a rapid fall or rapid rise of oxygen tension between room air (150 mm Hg) and 0 mm Hg ( a glucose oxidase/catalase solution) as well as the Clark electrode without encountering its technical problems; (2) with an acute hemorrhage to 20% of base line, the PsgO2 was found to decline rapidly in parallel with the decline of mean arterial pressure (MAP). Although the MAP rapidly returned to normal after immediate complete return of all shed blood, the PsgO2 did not reach normal levels for at least 2 hours, suggesting persistent peripheral vasoconstriction. (3) Studies in progress suggest that between 35 and 78% of trauma patients (n = 18) adequately resuscitated for hypovolemia b customary criteria have a decreased level of PsgO2 for as long as 60 hours after resuscitation for injury. If care is taken to prevent other causes of catecholamine induced vasoconstriction such as pain, fear, cold, and arterial hypoxia, these several results suggest that a certain number of injured patients are inadequately resuscitated despite the return to normal of conventional hemodynamic measurements. The serial analysis of PsgO2 may assist in managing patients and promote better understanding of the responses to injury.

Animals↗
PubMed1985

Interleukin-2 in rheumatoid arthritis: production of and response to interleukin-2 in rheumatoid synovial fluid, synovial tissue and peripheral blood.

Several aspects of interleukin-2 (IL-2) generation and function were studied employing mononuclear cells from synovial fluid (SF), synovial tissue (ST) and peripheral blood (PB) of patients with rheumatoid arthritis (RA). Decreased PHA stimulated IL-2 production by lymphocytes from rheumatoid ST, SF (P less than 0.02), and PB (P less than 0.01) was observed when compared to normal blood and SF of patients with gout. The proliferative response of rheumatoid lymphocyte blasts exposed to exogenous IL-2 was also defective (P less than 0.05-0.001). This defect was greater in SF than in rheumatoid PB (P less than 0.05-0.001). In addition to the proliferative response, the effect of IL-2 on interferon-gamma (IFN-gamma) production was also examined. Rheumatoid lymphocytes from both PB and SF produced less IFN-gamma after overnight treatment with IL-2 than did normal PB lymphocytes. This decreased IFN-gamma induction was discordant with the excellent enhancement by IL-2 of natural killer activity. Removal of adherent cells in synovial fluid did not correct this deficit. Abnormalities in the biology of IL-2 and IFN-gamma suggest that impaired T cell function could contribute to the immunopathogenesis of RA.

Adult↗
PubMedDate not supplied

Insulin resistance and vascular function.

It has become clear that amongst its many actions insulin is also a vasoactive hormone. Its effect to cause endothelial-nitric oxide-dependent vasodilation is physiologic and dose-dependent. Recent data suggest that insulin's metabolic and vascular actions are closely linked. Indeed, insulin resistant states, which by definition, exhibit diminished insulin-mediated glucose uptake into peripheral tissues also display impaired insulin mediated vasodilation as well as impaired endothelium dependent vasolidation to the muscarinic receptor agonist acetylcholine. Free fatty acids are elevated in states of insulin resistance and also cause endothelial dysfunction along with impaired insulin-mediated vasodilation. Thus, a picture is emerging linking insulin action in peripheral tissues to its action in endothelium. More recent data suggest that insulin signaling mechanisms in peripheral tissues and endothelium may be shared. Thus mechanisms causing insulin resistance via defects in insulin signaling might be expected to be manifest in both tissues. The protective action of nitric oxide and healthy endothelial function are critical to prevent atherosclerotic vascular disease. If follows that endothelial dysfunction associated insulin resistance through common defects in insulin signaling presents a parsimonious mechanism to account for the increased risk of cardiovascular disease associated with insulin resistance.

Blood Vessels↗
PubMed2004

Neural regulation of the hepatic circadian rhythm.

A microarray analysis experiment has revealed that there are many genes, including so-called clock genes, expressing a circadian rhythm in the liver. The clock genes mentioned above are expressed not only in the suprachiasmatic nucleus (SCN) of the hypothalamus, where the master clock exists, but also in other brain regions and various peripheral tissues. In the liver, clock genes are abundantly expressed and show a clear circadian rhythm. Thus, clock genes seem to play a critical role in the molecular clockworks of both the SCN and the liver. Although oscillation of clock genes in the liver is controlled under the circadian clock mechanism in the SCN, we do not know the resetting signals on liver clock function. Over the past few years, use of the pseudorabies virus, a transsynaptic tract tracer, has allowed us to map neural connections between the SCN and peripheral tissues in several physiological systems. Communication between the SCN and peripheral tissues occurs through autonomic nervous systems involving the sympathetic and parasympathetic neurons. This review mainly describes both anatomical and physiological experiments to reveal the sympathetic control over liver clock function. Although further study is necessary to produce the precise mechanism underlying neural control of liver clock systems, evolution of this mechanism will help our understanding of liver clock functions such as drug metabolism and energy metabolism.

Animals↗
PubMed1992

Structure and tissue-specific expression of 3 beta-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase genes in human and rat classical and peripheral steroidogenic tissues.

The enzyme 3 beta-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase (3 beta-HSD) catalyzes the oxidation and isomerization of 5-ene-3 beta-hydroxypregnene and 5-ene-hydroxyandrostene steroid precursors into the corresponding 4-ene-ketosteroids necessary for the formation of all classes of steroid hormones. We have recently characterized two types of human 3 beta-HSD cDNA clones and the corresponding genes which encode deduced proteins of 371 and 372 amino acids, respectively, and share 93.5% homology. The human 3 beta-HSD genes containing 4 exons were assigned by in situ hybridization to the p11-p13 region of the short arm of chromosome 1. We have also recently elucidated the structure of three types of rat 3 beta-HSD cDNAs as well as that of one type of 3 beta-HSD from bovine and macaque ovary lambda gt11 cDNA libraries which all encode 372 amino acid proteins. The human type I 3 beta-HSD is the almost exclusive mRNA species detected in the placenta and skin, while the human type II is the predominant mRNA species in the adrenals, ovaries and testes. The predicted rat type I and type II 3 beta-HSD proteins expressed in adrenals, gonads and adipose tissue share 94% homology while they share 80% similarity with the liver-specific type III 3 beta-HSD. Transient expression of human type I and type II as well as rat type I and type II 3 beta-HSD cDNAs in HeLa human cervical carcinoma cells reveals that 3 beta-ol dehydrogenase and 5-ene-4-ene isomerase activities reside within a single protein and these cDNAs encode functional 3 beta-HSD proteins that are capable of converting 3 beta-hydroxy-5-ene-steroids into 3-keto-4-ene derivatives as well as the interconversion of 3 beta-hydroxy and 3-keto-5 alpha-androstane steroids. We have found that the rat type III mRNA species was below the detection limit in intact female liver while, following hypophysectomy, its accumulation increased to 55% of the levels measured in intact or HYPOX male rats, an increase which can be blocked by administration of ovine prolactin (oPRL). In addition, in female rats, treatment with oPRL for 10 days starting 15 days after HYPOX, markedly decreased ovarian 3 beta-HSD mRNA accumulation accompanied by a similar decrease in 3 beta-HSD activity and protein levels. Treatment with the gonadotropin hCG reversed the potent inhibitory effect of oPRL on these parameters and stimulated 3 beta-HSD mRNA levels in ovarian interstitial cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1994

Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men.

It is well recognized that aging in men is accompanied by a decline in the serum levels of some adrenal and testicular steroids, but little or no attention has focused on the multiple steroid metabolites that are formed by steroid-converting enzymes in target tissues. In the present study, we have examined in detail the serum concentrations of a large series of adrenal and testicular steroids and their most significant metabolites produced in intracrine peripheral tissues. The serum concentrations of 26 conjugated and unconjugated C21-, C19-, and C18-steroids were measured in 2423 men aged 40-80 yr. The serum concentrations of the major circulating adrenal C19-steroids, namely dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), androst-5-ene-3 beta, 17 beta-diol and its sulfate, and androstenedione, decreased by about 60% between the ages of 40-80 yr. The small decrease in the serum concentrations of progesterone and pregnenolone in the presence of increased levels of cortisol and markedly decreased levels of DHEA, androst-5-ene-3 beta, 17 beta-diol, and their polar metabolites suggests that adrenal 17,20-lyase is particularly affected by aging. In addition to a marked decline in the serum concentrations of adrenal C19-steroids, a smaller, but significant, decrease occurred in serum testosterone. However, serum dihydrotestosterone levels remained constant, but the glucuronidated derivatives of dihydrotestosterone metabolites (androstane-3 alpha, 17 beta-diol glucuronide, androstane-3 beta, 17 beta-diol glucuronide, and androsterone glucuronide) were reduced by 45-50%, suggesting that 5 alpha-reductase activity in peripheral tissues may show a compensatory increase during aging. Analysis of the fatty acid esters of DHEA (DHEA-FA) also revealed that these nonpolar steroids markedly decrease between 40-80 yr of age, although such a decrease in DHEA-FA levels was smaller than that in DHEA and DHEA-S, suggesting that the formation of DHEA-FA may be specifically increased during aging. In summary, the present study suggests that in contrast to the marked decline in activity of steroidogenic enzymes in the adrenals and the small decrease in the testis, the activity of the steroid-converting enzymes present in peripheral tissues does not decrease during aging. In fact, the marked decrease in DHEA formation by the adrenals leads to a decrease of about 50% in total androgens in men between the ages of 40-80 yr. Such a decrease probably affects many physiological processes during aging.

Adrenal Glands↗
PubMed1993

Depletion of adipose tissue and peripheral nerve alpha-tocopherol in adult dogs.

To assess the relationship between tissue alpha-tocopherol depletion and histopathologic or functional changes in nervous tissue, a longitudinal study of male 1-year-old beagle dogs, two fed a vitamin E-deficient diet (0.05 +/- 0.02 mg alpha-tocopherol/kg;--E dogs) and two fed a vitamin E-supplemented diet (114 +/- 14 mg alpha-tocopherol/kg; +E dogs), was carried out. Plasma and adipose tissue alpha-tocopherol concentrations, neurological examinations, and sensory and motor nerve conduction velocities were determined at approximately 8-wk intervals over 109 wk. Tibial nerve alpha-tocopherol concentrations were measured at 65 and 109 wk; adjacent sections were examined for histologic changes. In the two -E dogs, plasma alpha-tocopherols declined linearly on a semilog plot to < 0.1 microgram/mL by 109 wk. Plasma alpha-tocopherol concentrations were depleted to half of the initial concentrations in approximately 87 d. Adipose tissue alpha-tocopherol concentrations (based on wet weight, cholesterol or triglyceride) also declined linearly on semilog plots, and were depleted to half of the initial concentrations in approximately 120 d. Tibial nerve alpha-tocopherols (ng/microgram cholesterol) in -E dogs decreased to 16% of average +E at 65 wk, and to 2% at 109 wk. Neurologic examinations, histologies and nerve conduction velocities were normal in all dogs throughout the study. Our results demonstrate in dogs that depletion of plasma, adipose tissue and nerve alpha-tocopherol precedes histologic and functional changes in peripheral nerves during vitamin E deficiency.

Adipose Tissue↗
PubMed1991

Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes.

A heterologous RIA method for pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38) and a homologous RIA method for a shorter form of PACAP with 27 residues (PACAP27) were established to determine PACAP content in central and peripheral tissues in rats. The highest concentration of radioimmunoassayable PACAP38 was found in the hypothalamus, but other brain regions also contained considerable amounts of PACAP38. PACAP38 concentration in the posterior pituitary was comparable with that in the extrahypothalamic brain, but its concentration in the anterior pituitary was very low. Unexpectedly, the testis contained a high abundance of PACAP38, and the total amount of PACAP in both testes exceeded its content in the whole brain. Reverse phase HPLC suggested that the major testicular PACAP38 immunoreactivity represents PACAP38. Among peripheral tissues, adrenal gland contained the second highest concentration of PACAP. Smaller amounts of PACAP were widely distributed in the digestive tract and other peripheral tissues. The concentration of PACAP in stomach, duodenum and jejunum appeared to be greater than in other portions of the gut. In all tissues, PACAP27 represented only a minor portion of total PACAP immunoreactivity.

Animals↗
PubMed2000

Hyperinsulinemia compensates for infection-induced impairment in net hepatic glucose uptake during TPN.

In animals receiving total parenteral nutrition (TPN), infection impairs net hepatic glucose uptake (NHGU) by 40% and induces mild hyperinsulinemia. In the normal animal, the majority of the glucose taken up by the liver is diverted to lactate, but in the infected state, lactate release is curtailed. Because of the hyperinsulinemia and reduced NHGU, more glucose is utilized by peripheral tissues. Our aims were to determine the role of infection-induced hyperinsulinemia in 1) limiting the fall in NHGU and hepatic lactate release and 2) increasing the proportion of glucose disposed of by peripheral tissues. Chronically catheterized dogs received TPN for 5 days via the inferior vena cava. On day 3, a fibrin clot with a nonlethal dose of E. coli was placed into the peritoneal cavity; sham dogs received a sterile clot. On day 5, somatostatin was infused to prevent endogenous pancreatic hormone secretion, and insulin and glucagon were replaced at rates matching incoming hormone concentrations observed previously in sham or infected dogs. The TPN-derived glucose infusion was adjusted to maintain a constant arterial plasma glucose level of approximately 120 mg/dl. after a basal blood sampling period, the insulin infusion rate was either maintained constant (infected time control, Hi-Ins, n = 6; sham time control, Sham, n = 6) or decreased (infected + reduced insulin, Lo-Ins; n = 6) for 180 min to levels seen in noninfected dogs (from 23 +/- 2 to 12 +/- 1 microU/ml). Reduction of insulin to noninfected levels decreased NHGU by 1.4 +/- 0.5 mg x kg(-1) x min(-1) (P < 0.05) and nonhepatic glucose utilization by 4.8 +/- 0.8 mg x kg(-1) x min(-1) (P < 0.01). The fall in NHGU was caused by a decline in HGU (Delta-0.6 +/- 0.4 mg x kg(-1) x min(-1)) and a concomitant increase in hepatic glucose production (HGP, Delta0.8 +/- 0.5 mg x kg(-1) x min(-1)); net hepatic lactate release was not altered. Hyperinsulinemia that accompanies infection 1) primarily diverts glucose carbon to peripheral tissues, 2) limits the fall in NHGU by enhancing HGU and suppressing HGP, and 3) does not enhance hepatic lactate release, thus favoring hepatic glucose storage. Compensatory hyperinsulinemia plays a critical role in facilitating hepatic and peripheral glucose disposal during an infection.

Animals↗
PubMed2002

Interorgan exchange of aminothiols in humans.

In the present study, we used organ balance across the kidney, splanchnic organs, and lower limb in subjects undergoing diagnostic central venous catheterizations to gain insight into the renal and extrarenal exchange of aminothiols in humans. Although Hcy was released only in low amounts from leg tissues, Cys-Gly (a peptide derived from GSH hydrolysis) was released by both the leg and splanchnic organs, whereas Cys was released by the kidney and taken up by splanchnic organs. The kidney removed approximately 90% of the Cys-Gly released into the circulation. Removal of Cys-Gly by the kidney depended on Cys-Gly arterial levels and showed a high fractional extraction ( approximately 26%), with clearance rates slightly higher than the glomerular filtration rate (GFR). Although the average kidney removal of Hcy was not statistically significant, the fractional extraction of Hcy across the kidney varied directly with renal plasma flow. Our data show that thiol metabolism in humans is a compartmentalized interorgan process involving fluxes of individual aminothiols that are parallel and of opposite sign among peripheral tissues, splanchnic organs, and kidney. Cys-Gly is released by peripheral tissue and splanchnic organs from GSH hydrolysis and is taken up by the kidney by GFR; the kidney returns Cys to the circulation to preserve substrate availability for GSH synthesis. On the other hand, Hcy is released by peripheral tissues in low amounts, and its removal by the kidney seems to depend on blood supply. These findings may help explain several alterations in aminothiol metabolism observed in patients with chronic diseases.

Adult↗
PubMed1995

Modulation of interleukin-1 receptors in the brain-endocrine-immune axis by stress and infection.

We summarize data from some of our recent studies on in vitro and in vivo modulation of interleukin-1 (IL-1) receptors in the mouse brain-endocrine-immune axis by stress and infection. Ether-laparotomy stress in mice resulted in a selective increase in pituitary IL-1 receptors and a significant decrease in pituitary receptors for corticotropin-releasing factor (CRF), a major regulator of the endocrine response to stress. Intraperitoneal injection of rat/human CRF mimicked the effects of stress and resulted in a dramatic increase in [125I]IL-1alpha binding in the pituitary; [125I]IL-1alpha binding in the hippocampus, spleen, and testis was unaffected by stress or CRF treatment. Glucocorticoid treatment with dexamethasone alone did not alter [125I]IL-1alpha binding but significantly inhibited CRF-induced upregulation of IL-1 receptors in the pituitary. The intracellular mechanism(s) involved in stress and CRF-induced upregulation of IL-1 receptors in the pituitary gland were examined by evaluating the effects of treatment of AtT-20 mouse pituitary corticotroph cells with a variety of neuroendocrine mediators of stress. CRF, forskolin, and isoproterenol (beta2 adrenergic receptor agonist) produced dose-dependent increases in cAMP production and [125I]IL-1alpha binding. In contrast, somatostatin and dexamethasone significantly inhibited CRF-stimulated increase of cAMP production and [125I]IL-1alpha binding, suggesting a primary role for cAMP in the regulation of pituitary IL-1 receptors. Next, we investigated the modulation of IL-1beta levels and IL-1 receptors following infection of mice with the endotoxin, lipopolysaccharide (LPS). Acute administration of low doses of endotoxin (30 mu g LPS/mouse) dramatically increased IL-1beta levels and reciprocally decreased [125I]IL-1alpha binding in peripheral tissues (pituitary, testis, liver, and spleen) but not in brain (hippocampus). This effect appeared to be dose related since higher doses of endotoxin (300 mu g LPS/mouse) significantly decreased [125I]IL-1alpha binding in both peripheral tissues and brain. Endotoxin induced modulation of the IL-1 system was also dependent on the treatment regimen since two low-dose LPS injections (at 0 and 12 h) increased IL-1beta concentrations and decreased [125I]IL-1alpha binding in both central and peripheral tissues. These data provide further support for a role for IL-1 in coordinating brain-endocrine-immune responses to stress and infection.

Anesthetics, Inhalation↗
PubMed1998

Kinetics of productive and latent HIV infection in lymphatic tissue and peripheral blood during triple-drug combination therapy with or without additional interleukin-2.

OBJECTIVE: To study decay rates of productively and latently infected cells in peripheral blood and lymph nodes during triple antiretroviral therapy and the possible impact of interleukin-2 (IL-2) on viral kinetics. METHODS: In this non-randomized study, nine antiretroviral-naive HIV-positive patients received either saquinavir hard gel capsules 2400 mg three times daily (group I; four patients) or saquinavir soft gel capsules 1200 mg three times daily and IL-2 (group II), in both cases together with two nucleoside analogues. Plasma viraemia and lymphocyte subsets were analysed. Axillary lymph nodes were excised before and after 12 weeks of therapy. Lymph node sections were examined by in situ hybridization for HIV RNA, and productively infected cells were counted. Infection rates of FACS-sorted CD3, CD4 lymph node and peripheral blood mononuclear cells were determined by nested DNA PCR. RESULTS: Baseline plasma HIV RNA levels ranged from < 25 to > 1 x 10(6) copies/ml and remained undetectable throughout the study in one patient in group I. Plasma viraemia became undetectable after 3 months in four patients (three in group I). Productively infected cells were markedly reduced in the follow-up lymph node specimens. HIV DNA-positive CD4 T cells were reduced in lymphoid tissue and peripheral blood in all six evaluable patients. There were no significant differences between the groups in the clearance rates of plasma virus and of HIV DNA-positive cells. CONCLUSIONS: Combined antiretroviral therapy rapidly suppressed active HIV replication in plasma and lymphoid tissue. Latently infected cells were cleared at a slower rate. Viral clearance did not appear to be markedly affected by additional IL-2 therapy.

Adult↗