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PubMed2001

Pegylated cytokines: potential application in immunotherapy of cancer.

Conjugation of the polymer polyethylene glycol (PEG) to proteins can significantly decrease their clearance from plasma, thus increasing their half-lives in vivo. The increased half-life of PEG-proteins is directly proportional to the total molecular weight of the construct. This approach has been used to design cytokine constructs that can be administered once a week, rather than on a daily or alternate-day schedule. Two cytokines for which this approach appears to be successful are PEG-interferon-alpha-2a (PEG-IFNalpha-2a) and PEG-granulocyte colony- stimulating factor (PEG-G-CSF). Both use high molecular weight PEG (20 to 40kD) to give sufficiently long duration in vivo. In the case of PEG-G-CSF conjugates, the in vivo efficacy is directly proportional to molecular weight, whereas the in vitro activity is inversely proportional, suggesting that overall duration of contact is more important than the affinity of the interaction. Conjugates of a number of other cytokines have been prepared, but until recently, few have used the high molecular weight polymers. In the future, as this approach is taken to make new PEG-cytokine constructs, thorough pharmacokinetic studies will be essential for their development and clinical use.

Animals↗
PubMed1997

Activity of thymidine kinase and of polymerase alpha as well as activity and gene expression of deoxycytidine deaminase in leukemic blasts are correlated with clinical response in the setting of granulocyte-macrophage colony-stimulating factor-based priming before and during TAD-9 induction therapy in acute myeloid leukemia.

The present study was undertaken to assess the predictive value of pretherapeutic determinants of ara-C metabolism and proliferative activity of leukemic blasts for early response to antileukemic therapy in the setting of granulocyte-macrophage colony-stimulating factor (GM-CSF)-based priming before and during TAD-9 induction in 36 consecutive patients with de novo acute myeloid leukemia (AML). Ara-C metabolism was assessed by the activities of deoxycytidine kinase (DCK), deoxycytidine deaminase (DCD), DNA polymerase alpha (Poly alpha), and overall polymerase (overall Poly). The fraction of cells in S phase (%S phase) and thymidine kinase (TK) activity were determined as a measure of proliferative activity. Early response to therapy was defined by the percentage of leukemic blasts in the bone marrow 5 to 7 days after completion of TAD-9 with less than 5% signaling an adequate response and greater than 5% indicating an inadequate early reduction, respectively. While neither %S phase, DCK, nor overall Poly activity were predictive for early response, TK and Poly alpha activities were significantly higher for cases with adequate blast cell clearance. The respective median values were for TK 3.8 versus 1.85 pmol/min/mg protein (P = .012), and for Poly alpha 1.9 versus 0.69 pmol/min/mg protein (P = .014). An inverse relation was detected for DCD activity which was significantly lower in responding patients with a median of 0.33 nmol/min/mg protein (range, 0.0 to 29.5) as compared to a median of 5.1 nmol/min/mg protein (range, 0.11 to 8.45) in early nonresponders, (P = .009). Taking the respective median values as arbitrary cut-points for high or low enzyme activities, responders and nonresponders could be discriminated prospectively. Hence, 14 of 16 cases (88%) with DCD activities below the median of 1.56 nmol/min/mg protein responded as compared to only 3 of 14 (22%) patients with higher DCD activities (P = .0004). From the 15 patients with TK activity above the overall median of 3.2 pmol/min/mg protein, 11 cases (73%) achieved an adequate blast cell clearance while only 6 of 17 cases (35%) with lower values responded (P = .035). Similarly, 12 of 15 patients (80%) with high Poly alpha levels (>1.22 pmol/min/mg protein) responded to induction therapy as compared to only 5 of 14 patients (36%) with lower enzyme activities (P = .02). By logistic regression analysis of enzyme activities, DCD activity was found to be the most sensitive parameter to predict an adequate blast cell clearance (P = .032). Activities of DCD and TK were not only associated with initial response but were also found predictive for remission duration. Hence, from 11 patients with low TK levels 8 (73%) relapsed within 1 year, whereas only 2 of 11 (18%) patients with high TK activity experienced a recurrence of their disease (P = .015). Six of 9 (66%) patients with higher than median DCD levels relapsed within 1 year, whereas 10 of 14 patients (71%) with lower DCD levels had a longer remission duration (P = .085). Analysis of DCD gene expression at the mRNA level by a semi-quantitative reverse transcriptase-polymerase chain reaction method showed that a high transcription rate of the DCD gene was associated with high enzyme activities and vice versa. Hence, the observed intraindividual differences in DCD activity are a reflection of differences in gene activity and transcription rate rather than of variants in translation. Although further analyses are needed to elucidate the molecular mechanisms that determine the variation of enzyme activities in individual patients, the present study strongly suggests that pretherapeutic determination of TK and Poly alpha as well as of DCD allows to predict response to TAD-9 + GM-CSF induction therapy and may provide the means for the development of a risk adapted treatment strategy.

Acute Disease↗
PubMed1998

Circulating leptin level and growth hormone response to stimulation tests in obese and normal children.

OBJECTIVE: Growth hormone secretion is decreased in obese subjects, and their GH response to stimulation tests is blunted. The mechanisms relating excess adipose mass and GH secretion are unknown. We hypothesized that leptin might be a signal linking adipose mass to GH secretion. DESIGN: We measured serum leptin levels and the GH response to stimulation tests in 42 obese and 40 lean short normal prepubertal children. RESULTS: The mean serum leptin concentrations were 23.8+/-1.7 ng/ml and 3.6+/-0.4 ng/ml in obese and lean children respectively, and were found to be inversely related to GH peak in both groups. After adjusting for body fat data, leptin was still an independent predictor of GH peak. Multiple stepwise regression analysis identified both leptin (regression coefficient = -0.78, P = 0.001), and insulin (regression coefficient = -0.03. P = 0.009) as negative determinants of GH response to the GHRH test in obese children (multiple R = 0.64), and only leptin in lean children (r = -0.51, P = 0.001). No correlation was observed between leptin and IGF-I or IGF binding protein-3. CONCLUSION: These results are consistent with the hypothesis that leptin could contribute to the regulation of GH secretion.

Adolescent↗
PubMed1994

Insulin-like growth factor-binding protein-1 is correlated with low density lipoprotein cholesterol in normal subjects.

Insulin-like growth factor-I (IGF-I) has been inversely associated with low-density lipoprotein (LDL) cholesterol in normal women with slightly elevated cholesterol levels and hypothyroid women. More than 95% of IGF-I circulates bound to binding proteins (IGFBPs); of these IGFBP-1 is of particular interest as it is inversely regulated by insulin and is thought to inhibit the action of IGF-I and IGF-II. We examined the relationship between IGFBP-1 and LDL cholesterol in 41 healthy adult subjects. LDL cholesterol correlated with the body mass index (r = 0.40, P < 0.01), sex (r = 0.51, P < 0.001) and IGFBP-1 levels (r = 0.36, P < 0.02). LDL cholesterol did not correlate with age (r = 0.25, P = not significant) or IGF-I (r = 0.06, P = not significant). Upon multivariate regression analysis, sex, body mass index and IGFBP-1 were all independent predictors of LDL cholesterol (all P < 0.05). Elevated IGFBP-1 levels have been associated with an inhibition of serum IGF-I bioactivity in children with insulin-dependent diabetes. IGFBP-1 also appears to inhibit IGF-I hexose-stimulated uptake. IGFBP-1 may also be inhibiting the effect of IGFs on the cellular metabolism of LDL cholesterol.

Adult↗
PubMed1992

The pituitary control of rat thyroxine binding globulin.

Thyroxine-binding globulin (TBG) is in the rat a developmentally regulated protein, actively synthesized in postnatal developing pups and in aging animals, but undetectable in adults. Experimental depletion of thyroid hormones (TH) in adults by thyroidectomy (Tx) or by hypophysectomy (Hx) results in marked reexpression of TBG synthesis. T3 replacement in both cases antagonizes this effect, though only moderately in Hx rats. These observations point to a regulatory pathway of TBG synthesis common to TX and Hx rats, characterized by an inverse relationship between TBG and TH levels. However, along with this thyroid-dependent TBG regulation, important differences between Tx and Hx rats are evidenced, pointing to specific pituitary factors of TBG control. The most striking difference concerns the effect of growth hormone (GH) replacement: the TBG of Tx rats is not affected, in contrast to that of Hx rats which is further increased by GH administration. The TBG response of the GH-treated Hx rats, which is strongly resistant to inhibition by T3, might involve deshomeostasis of GH-controlled functions not necessarily linked to the thyroid, e.g. the pancreatic functions regulating carbohydrate or lipid metabolism. In the light of these studies, it may be envisaged that the high surge of rat TBG during postnatal development involves a transient sensitivity of the TBG gene to stimulation by endogenous GH, and that this sensitivity lasts until functional maturity of the hypothalamic-pituitary-thyroid axis has been achieved.

Animals↗
PubMed2002

Cloning and characterization of the 5'-flanking region of the canine growth hormone gene.

The growth hormone (GH) gene is expressed in a variety of tissues outside the pituitary, including the mammary gland. GH expression in the mammary gland is stimulated by progestins. The local synthesis of mammary GH may provide a highly proliferative environment within the mammary gland that may contribute to the development or progression of mammary tumours. To elucidate the mechanism regulating mammary GH expression, we cloned the 5'-flanking region of the canine GH gene using inverse polymerase chain reaction. Gel-shift experiments showed that several sequences in the 5'-flanking region of the GH gene bind mammary nuclear proteins and may be involved in basal and progesterone-induced mammary GH expression. Sequence analysis and comparison with the GH promoters of human, rat, and mouse genes revealed a number of shared binding sites for transcription factors such as Pit-1, which is involved in pituitary GH expression, and for factors involved in the differentiation of lymphoid cells. Moreover, a putative binding site for the progesterone receptor (PR) was identified in all promoters, indicating that the progestin-induced expression of GH in mammary tissue is most probably a direct effect of activated PRs on the GH gene promoter and that this may occur in various species.

5' Flanking Region↗
PubMed1993

The somatotropin-somatomedin axis in adult patients with Turner syndrome: measurement of stimulated GH, GH-BP, IGF-I, IGF-II and IGFBP-3 in 25 patients.

So far, few studies have addressed the regulation of GH and GH-dependent growth factors in adult patients with Turner syndrome. We therefore studied a group of 25 genetically proven patients with Turner syndrome (age 20-50 years) and 10 control women (25-48 years). Turner patients were significantly shorter (148.7 +/- 1.1 cm vs. 169.1 +/- 2.3 cm; mean +/- SE; p < 0.0001) and more overweight [body mass index (BMI)] 25.6 +/- 1.3 vs. 21.4 +/- 0.6 in controls; p < 0.01). No significant differences were present when the integrated GH response to stimulation with arginine and the serum levels of GH-binding protein (GH-BP), IGF-I, IGF-II and binding protein 3 for IGFs (IGFBP-3) were compared between the two groups. However, more detailed analysis revealed significant abnormalities of the somatotropic axis in Turner patients. Pituitary GH secretion was negatively and serum GH-BP positively related to the degree of overweight in normal patients. In Turner patients, no such relationship was present, while IGF-II significantly increased with BMI. IGFBP-3 was positively related to adult height in normal women but not in Turner patients. While serum testosterone values did not affect any of the somatotropic parameters measured, there was a previously unreported, inverse relation between serum estradiol and GH-BP in controls but not in Turner patients. While adult patients with Turner syndrome do not display endocrine features of GH insufficiency, a detailed analysis reveals several abnormalities of the interrelation between anthropometric parameters, sex steroids and the pituitary-somatomedin axis.

Adult↗
PubMed1995

Poly(dA:dT), a ubiquitous promoter element that stimulates transcription via its intrinsic DNA structure.

Many yeast promoters contain homopolymeric dA:dT sequences that affect nucleosome formation in vitro and are required for wild-type levels of transcription in vivo. Here, we show that poly(dA:dT) is a novel promoter element whose function depends on its intrinsic structure, not its interaction with sequence-specific, DNA-binding proteins. First, poly(dA:dT) stimulates Gcn4-activated transcription in a manner that is length dependent and inversely related to intracellular Gcn4 levels. Second, Datin, the only known poly(dA:dT)-binding protein, behaves as a repressor through poly(dA:dT) sequences. Third, poly(dG:dC), a structurally dissimilar homopolymer that also affects nucleosomes, has transcriptional properties virtually identical to those of poly(dA:dT). Three probes of chromatin structure including HinfI endonuclease cleavage in vivo indicate that poly(dA:dT) increases accessibility of the Gcn4 binding site and adjacent sequences in physiological chromatin. These observations suggest that, by virtue of its intrinsic structure, poly(dA:dT) locally affects nucleosomes and increases the accessibility of transcription factors bound to nearby sequences.

Base Sequence↗
PubMed2004

Hexavalent chromium reduction by an actinomycete, arthrobacter crystallopoietes ES 32.

Environmental contamination by hexavalent chromium, Cr(VI), presents a serious public health problem. This study assessed the reduction of Cr(VI) by intact cells and a cell-free extract (CFE) of an actinomycete, Arthrobacter crystallopoietes (strain ES 32), isolated from soil contaminated with dichromate. Both intact cells and CFE of A. crystallopoietes, displayed substantial reduction of Cr(VI). Intact cells reduced about 90% of the Cr(VI) added within 12 h and Cr(VI) was almost completely reduced after 24 h. The KM and Vmax of Cr(VI) bioreduction by intact cells were 2.61 microM and 0.0142 micromol/min/mg protein, respectively. Cell-free chromate reductase of the A. crystallopoietes (ES 32) reduced hexavalent chromium at a KM of 1.78 microM and a Vmax of 0.096 micromol/min/mg protein. The rate constant (k) of chromate reduction was inversely related to Cr(VI) concentration and the half-life (t1/2) of Cr(VI) reduction increased with increasing concentration. A. crystallopoietes produced a periplasmic chromate reductase that was stimulated by NADH. Results indicate that A. crystallopoietes ES 32 can be used to detoxify Cr(VI) in polluted sites, particularly in stressed environments.

Actinobacteria↗
PubMed1992

Differential stability of mRNAs coding for alpha and gonadotropin beta subunits in cultured rat pituitary cells.

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) result from the assembly of a common subunit alpha and a unique subunit beta, expressed in the same cell by single, structurally-related genes. In order to compare the intrinsic stability of the alpha, LH beta and FSH beta mRNA transcripts, we used cultured rat pituitary cells incubated in presence of actinomycin D. Hybridization with 32P-labelled rat cDNA probes showed that the cell content of all three mRNAs decreased with time, but at different rates. Apparent half-lives, estimated as the time necessary to observe a 50% mRNA decay, were 1.0 +/- 0.13 h for FSH beta, 6.5 +/- 0.25 h for alpha and 44 +/- 0.5 h for LH beta, stability thus exhibiting an inverse relation to the sizes of the corresponding mRNAs (approximately 1700, 800 and 700 nucleotides, respectively). Northern analysis revealed that the decline in mRNA abundance was associated with a progressive decrease in the length of mRNAs, most clearly visible for alpha and LH beta. For the most stable LH beta mRNA, shortening was apparent as early as 2 h after exposure to actinomycin D thus preceding neatly the decrease in amount starting at about 10-12 h. In vitro RNase H digestion demonstrated that shortening resulted from a reduction of the length of the poly(A) tract. These data establish that the three mRNAs coding for gonadotropin subunits have different stabilities although they share substantial homology. Diversity in size and sequence essentially resides in untranslated regions in which, we suggest, specific motifs and protein factors may interact to determine mRNA stability.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Neurotrophin receptor p75(NTR) suppresses growth and nerve growth factor-mediated metastasis of human prostate cancer cells.

The loss of tumor- and/or metastasis-suppressor gene function contributes to the transformation of human prostate epithelial cells to a malignant pathology. Such a putative tumor-suppressor and metastasis-suppressor gene(s) has been mapped to the region of 17q21, which coincidentally is in the vicinity of the human gene locus for the neurotrophin receptor p75(NTR). The p75(NTR) is expressed in normal human prostate epithelial cells and exhibits an inverse association of p75(NTR) expression with the malignant progression of the prostate, consistent with a pathologic role of the p75(NTR) as a putative tumor and metastasis suppressor. Utilizing stable transfectants of the TSU-pr1 and PC-3 human prostate tumor cell lines that exhibit a rank order (dose-dependent) increase in p75(NTR) protein expression, we investigated the effects of the p75(NTR) in combination with its predominant ligand, nerve growth factor (NGF), on tumor cell growth. A rank order (dose-dependent) increase in p75(NTR) expression was found to suppress the growth of prostate tumors in severe combined immunodeficient (SCID) mice. Treatment of these tumors with NGF stimulated both proliferation as indicated by PCNA expression and apoptosis as indicated by TUNEL assay, the net result of which was no change in the overall growth of the tumors. However, NGF was found to increase the formation of satellite tumors, both contiguous and noncontiguous with respect to the primary tumor mass, indicating dose-dependent induction of metastasis. Significantly, the formation of satellite tumors was suppressed by the expression of p75(NTR). This suggests that p75(NTR) is a tumor suppressor of growth and a metastasis suppressor of NGF-stimulated migration of human prostate tumor cells.

Animals↗
PubMed1984

Tissue factor activity. A marker of alveolar macrophage maturation in rabbits. Effects of granulomatous pneumonitis.

Experiments were carried out to examine relationships between alveolar macrophage maturity and amounts of tissue factor (Clotting Factor III) in these cells under physiologic conditions and during immunologically induced pneumonitis. Using discontinuous density gradient centrifugation, alveolar macrophages from healthy rabbits were rapidly isolated into five subpopulations at different stages of maturation, as demonstrated by morphologic and morphometric evaluation. Very large amounts of tissue factor activity were found in fully mature cells that were purified in the lowest density subpopulation and assayed without preliminary in vitro stimulation or culture. In the remaining four subpopulations of increasing density, amounts of tissue factor were found to progressively diminish in direct correlation with declines of cell maturity. These differences at mean levels were as great as 35-fold. In addition, blood monocytes had less than 1/219 and less than 1/6 of the activity of the fully mature and the least mature subpopulations, respectively. After 16 h culture of the five isolated subpopulations in the absence of lymphokines or of significant numbers of lymphocytes, tissue factor activity increased in inverse correlation with the preincubation stage of cell maturity (2,387 and 109% in the least mature and most mature subpopulations, respectively). These increases required protein synthesis and were accompanied by morphologic and morphometric changes which indicated cellular maturation during the period of tissue factor activity generation in vitro, thus further demonstrating relationships between macrophage maturity and tissue factor content. In additional experiments, direct correlations between cell maturity and tissue factor activity content were also found in activated alveolar macrophage populations from rabbits with Bacillus Calmette Guering (BCG)-induced granulomatous pneumonitis. However, as compared with controls, the BCG populations had increased total amounts of tissue factor activity due to the presence of large numbers of mature alveolar macrophage forms that had high levels of the procoagulant. Thus, tissue factor activity in alveolar macrophages is a marker of cellular maturation in vivo and in vitro. Increased amounts of this initiator of the extrinsic clotting pathway, as found in alveolar macrophage populations from animals with granulomatous pneumonitis induced by BCG hypersensitivity, suggest that alveolar macrophage tissue factor may contribute to the pathology of immune lung diseases.

Animals↗
PubMed1994

IHF supresses the inhibitory effect of H-NS on HU function in the hin inversion system.

In the hin-mediated DNA inversion system, HU facilitates formation of the synaptic complex composed of two recombination sites spaced 996 bp apart and of the enhancer situated between them, by looping the DNA as to promote interaction of Hin invertase with the Fis enhancer factor [Johnson et al., Nature 329 (1987) 462-465]. The HU requirement for the in vivo hin-mediated inversion was demonstrated previously [Wada et al., Gene 76 (1989) 345-352; Hillyard et al., J. Bacteriol. 172 (1990) 5402-5407; Haykinson and Johnson, EMBO J. 12 (1993) 2503-2512] and in the current experiments. This HU action, however, required IHF when H-NS was present in the cell; i.e., the inversion reaction of the hin-invertible DNA fragment carried by the pKK1202R plasmid proceeded efficiently in host cells either deficient in H-NS or in the presence of both H-NS and IHF, but not in the cells depleted for IHF alone. The level of hin mRNA in mutant cells lacking HU or IHF, in which hin inversion did not occur, was normal or slightly increased. When IHF was absent, the stimulating effect of HU on in vitro DNA circle formation of a 125-bp hin fragment between hixL and the enhancer where Fis binds was inhibited by H-NS. The present study provides an example of a multi-component interaction between HU, H-NS and IHF on the hin DNA region, which contains three characteristic sites, a d(A/T)4 stretch and bent DNA site, and two putative IHF-binding sites.

Bacterial Outer Membrane Proteins↗
PubMed2005

[Expression of T-bet and its relation with IgE and eosinophil cationic protein in patients with allergic rhinitis].

OBJECTIVE: To investigate the expression of T-bet mRNA in peripheral blood mononuclear cells (PBMC) as well as its relations with total IgE (TIgE), eosinophil cationic protein (ECP) in serum and nasal allergic symptoms in patients with allergic rhinitis (AR). METHODS: The allergen, TIgE and ECP in serum of patients with AR were detected by Unicap CAP system. Blood sample was taken from 8 healthy individuals and 22 patients with allergic rhinitis. PBMC was isolated by density gradient centrifugation and one part of them was cultured with 50 microg/ml mite allergen. PBMC was subjected to analysis of T-bet mRNA expression using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: The ratio of T-bet to beta-actin mRNA levels was 0.381 +/- 0.099 in patients and 0.750 +/- 0.067 in normal individuals, the difference was significantly (P <0.01). The expression intensity of T-bet mRNA had no relation to varying severity of allergic symptoms and concentration of ECP and the correlation coefficient was 0.187 and -0.165 (all P > 0.05). However, there was an inverse correlation between expression intensity of T-bet mRNA and TIgE concentration (r = -0.525, P < 0.05). Mean mRNA level (x +/- s) of T-bet expression before and after being stimulated by allergen was 0.381 +/- 0.099 and 0.365 +/- 0.104 respectively, which indicated no significant differences (P > 0.05). CONCLUSIONS: Among allergic patients whose allergen was mite, there was a down-regulated expression of T-bet mRNA, which had no relation to ECP concentration and allergic symptoms, but was one of important links in mechanisms of imbalance of Th1/Th2 in AR. There was no effect of specific allergen on T-bet mRNA in patients with AR T-bet was one of indirect factors that affected the level of IgE.

Adolescent↗
PubMed2001

p21(WAF1) and transforming growth factor-alpha mediate dietary phosphate regulation of parathyroid cell growth.

BACKGROUND: The parathyroid (PT) hyperplasia induced by renal failure can be further enhanced by high dietary phosphate (P) or completely abolished by P restriction. To identify potential mechanisms mediating these opposing effects of dietary P on PT growth, this study first focused on p21(WAF1) (p21) because high P reduces while low P enhances serum 1,25-dihydroxyvitamin D, whose potent antiproliferative properties result from the induction of p21. In addition to reducing p21, high P-induced PT growth could result from increased PT expression of the growth promoter transforming growth factor-alpha (TGF-alpha), known to be elevated in hyperplastic and adenomatous human PT glands. METHODS: The time course for dietary P regulation of PT expression of TGF-alpha and p21 was assessed for seven days after 5/6 nephrectomy in rats and correlated with the degree of PT hyperplasia and secondary hyperparathyroidism. RESULTS: In P-restricted 5/6 nephrectomized rats, PT-p21 mRNA and protein increased by day 2, independent of changes in serum 1,25-dihydroxyvitamin D, and remained higher than in the high P counterparts for up to seven days. The PT hyperplasia of the high P group could not be attributed to a reduction of PT-p21 expression from normal control values. Instead, PT-TGF-alpha protein was higher in uremic rats compared with normal controls and increased further with high dietary P intake. PT levels of proliferating cell nuclear antigen (PCNA), an index of cell mitoses, correlated inversely with p21 and directly with TGF-alpha. Consistent with these findings, PT gland size and serum PT hormone levels, similar in both dietary groups at day 2, were higher in the high P group by day 5. Induction of p21 by low P and of TGF-alpha by high P was specific for the PT glands. Dietary P had no effect either on intestinal growth or p21 or TGF-alpha protein content. CONCLUSIONS: These findings suggest that low P induction of p21 could prevent PT hyperplasia in early uremia, whereas high P enhancement of TGF-alpha may function as an autocrine signal to stimulate growth further.

Animals↗
PubMed1995

Cytokines and progenitor cells of granulocytopoiesis in peripheral blood of patients with bacterial infections.

To investigate the physiological role of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adaptation mechanisms of myelopoiesis to enhanced demand, we studied both cytokines and their myeloid target cells in hematologically healthy patients suffering from acute bacterial infections. Endogenous serum levels of G-CSF and GM-CSF, granulocyte-macrophage colony-forming cell (GM-CFC) concentrations, and differential counts were determined for the peripheral blood of 57 patients with clinically apparent bacterial infections (26 males and 31 females aged 16 to 89 years) and 18 healthy controls (8 males and 10 females aged 23 to 84 years). Patients were selected for acute-phase protein and at least two additional clinical signs reflecting a bacterial infection. Patients showed significantly higher numbers of myeloid progenitor cells than controls (median, 68 versus 26 GM-CFC/ml; P < or = 0.01). G-CSF but not GM-CSF levels were found to be elevated (> or = 50 to 863 pg/ml). In the acute stage of infection, progenitor and cytokine levels were not influenced by gender, differences in therapy, or localization of the infection. Progenitor and G-CSF levels were not associated with absolute neutrophil counts or C-reactive protein. However, a negative correlation between number of GM-CFC per milliliter and age (R = -0.47; P < or = 0.001) and an inverse relationship between the incidence of high GM-CFC concentrations and elevated G-CSF levels (phi = -0.34; P < or = 0.01) were found. Combining both parameters into a cytokine-progenitor pattern, we observed a highly significant age-dependent response of myelopoiesis to inflammation (P < or = 0.001). Younger patients had high progenitor counts (> 75 GM-CFC/ml) associated with G-CSF levels below 50 pg/ml, whereas for the older patients, the reverse pattern was predominant. The results indicate that the age-dependent myelopoietic response to acute bacterial infections is characterized by an inverse relationship between progenitor cells and G-CSF. The observed cytokine-progenitor patterns could have implications for therapy with G-CSF and the prognosis of infectious diseases.

Adolescent↗
PubMed1997

Demonstration of a leptin binding factor in human serum.

Serum leptin levels are elevated in subjects with exogenous obesity, indicating that obesity is associated with leptin resistance. Since in man no abnormalities have yet been found in either the genes for leptin or its receptor, the mechanism of leptin resistance in obesity remains unknown. To determine if resistance might be related to leptin binding by a serum component, we assessed the carrier status of leptin in serum. The presence of a specific leptin binding factor in human serum has been established by (1) demonstrating [125I]-leptin binding to a serum component that is saturable and specifically displaceable only by unlabeled leptin and not by human growth hormone, pork insulin, insulin-like growth factors I and II, luteinizing or follicle stimulating hormones, transforming growth factor-beta 1, interleukin-6, or leukemia inhibiting factor; (2) fractionating the leptin bound serum complex and the serum leptin binding component on a molecular sieving column revealing a mass of approximately 450 kDa; and (3) identifying an inverse correlation between the concentration of serum leptin and the quantity of the leptin binding component. It is suggested that binding of leptin by this serum component may influence the physiologic response to leptin.

Animals↗
PubMed2000

Role of heat shock proteins in gastric mucosal protection.

Heat shock proteins (HSP) are crucial for the maintenance of cellular homeostasis during normal cell growth and for survival during and after various cellular stresses. Gastric surface mucous cells are the first line of defence against insults derived from ingested foods and Helicobacter pylori infection. Primary cultures of gastric surface mucous cells from guinea-pig fundic glands exhibited a typical heat shock response after exposure to elevated temperature or metabolic insults, such as ethanol and hydrogen peroxide, and they were able to acquire resistance to these stressors. Restraint and water immersion stress rapidly activated heat shock factor 1 (HSF1) in rat gastric mucosa within 15 min and induced HSP70 mRNA expression and its protein accumulation. The extent of the induction inversely correlated with the severity of mucosal lesions, suggesting an important role of HSP70 in gastric mucosal defence. This heat shock response appeared to be mediated by the alpha1A-adrenoceptor. The HSP70 family functions as a molecular chaperone and reduces stress-induced denaturation and aggregation of intracellular proteins. In addition to its chaperoning activities, HSP70 has been suggested to exert its cytoprotective action by protecting mitochondria and by interfering with the stress-induced apoptotic programme. Recently, we introduced geranylgeranylacetone as a non-toxic HSP70 inducer. This compound weakly stimulated HSP70 induction in cultured gastric mucosal cells and gastric mucosa by directly activating HSF1 and markedly augmented HSP70 induction in response to subsequent exposure to stress. Thus, non-toxic HSP70 inducers may have a potential benefit for the prevention and treatment of stress ulcer.

Animals↗