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Query: UNIPROT:P06889 (Mol)
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T-lymphocyte (T-LC)-derived cytokines have been implicated in asthma pathogenesis. Activation of peripheral blood CD4 but not CD8 T-LC and a Th2-type pattern of elevated cytokine mRNA expression in BAL fluid T-LC have been observed in asthmatics, but the principal source (CD4 or CD8 T-LC) of these cytokines is unknown. Our objective was to measure expression of Th1- and Th2-type cytokine mRNA and spontaneous secretion of IL-3, IL-5, and GM-CSF by peripheral blood CD4 and CD8 T-LC from asthmatics before and after oral glucocorticoid therapy and non-asthmatic controls. We used in situ hybridization to detect mRNA expression in isolated CD4 and CD8 T-LC, and an in vitro eosinophil survival assay to detect secretion of IL-3, IL-5, and GM-CSF in T-LC culture supernatants. Comparing the asthmatics with the controls, elevated percentages of CD4 T-LC expressed mRNA encoding IL-5, IL-4, and GM-CSF (P < 0.02) but not IL-3, IL-2, or IFN-gamma. In CD8 T-LC, mRNA expression was generally low with no significant differences between the groups. In the asthmatics, the percentages of CD4 T-LC expressing IL-5 mRNA correlated with disease severity and the numbers of peripheral blood eosinophils (P < 0.01). Culture supernatants of asthmatic CD4 but not CD8 T-LC exhibited significantly higher (P = 0.0003) eosinophil survival-prolonging activity compared with controls, in which low activity was detected. Inhibition with anti-cytokine antibodies suggested that GM-CSF, and to a lesser extent IL-5 and IL-3, could account for this activity. After oral glucocorticoid therapy of the asthmatics, lung function improved and the percentages of CD4 T-LC expressing mRNA encoding IL-3, IL-5, and GM-CSF but not IL-2, IL-4, or IFN-gamma were reduced (P < 0.04). Secretion of eosinophil survival-prolonging activity by the CD4 T-LC was also reduced (P = 0.004). We conclude that peripheral blood CD4 but not CD8 T-LC from asthmatics express cytokine mRNA in a Th2-type pattern and show elevated secretion of cytokines prolonging eosinophil survival. Glucocorticoid therapy of asthmatics is associated with a reduction in the percentages of CD4 T-LC expressing IL-3, IL-5, and GM-CSF mRNA and secretion of the corresponding proteins.
Am J Respir Cell Mol Biol 1995 May
PMID:Peripheral blood CD4 but not CD8 t-lymphocytes in patients with exacerbation of asthma transcribe and translate messenger RNA encoding cytokines which prolong eosinophil survival in the context of a Th2-type pattern: effect of glucocorticoid therapy. 774 19

Pulmonary vascular sequestration of leukocytes has been reported to increase in some models of lung injury, including that induced by gram-negative bacterial lipopolysaccharide (LPS). Neutrophils recruited to the lung likely participate in LPS-induced lung inflammation and associated injury, but the functional activities of these pulmonary vascular neutrophils have not been directly assessed. In the current study, cells were recovered by pulmonary vascular lavage (PVL) of isolated rat lungs, harvested 2 h after intravenous infusion of LPS (3 mg/kg) or saline in intact rats, at which time LPS-induced neutrophil recruitment to the lung could be appreciated histologically but not by airway lavage. Relative concentrations of leukocytes recovered from the pulmonary vasculature by PVL were compared with those present in circulating blood, normalizing for lavage dilution on the basis of erythrocyte counts. Excess neutrophils, lymphocytes, monocytes, and eosinophils were recovered from the pulmonary vasculature of controls, and LPS infusion increased recovery of neutrophils (most prominently), lymphocytes, and monocytes. Compared with cells recovered from controls, PVL neutrophils from LPS-infused animals were primed for increased zymosan-stimulated superoxide generation, determined by ferricytochrome C reduction, and were more adherent to nylon wool columns. Northern blots of extracted RNA demonstrated that LPS infusion also upregulated interleukin-1 beta (IL-1 beta) mRNA expression in PVL leukocyte samples, but not BAL or circulating blood samples. Ficoll-hypaque separation demonstrated that the LPS-induced IL-1 beta signal in PVL leukocytes was derived primarily from polymorphonuclear rather than mononuclear leukocytes. In conclusion, all circulating leukocyte populations are sequestered in rat lungs, and LPS increases pulmonary vascular sequestration of leukocytes, recruiting most prominently an activated pool of neutrophils that are more adherent, primed for increased oxygen radical production, and expressing increased IL-1 beta message. These findings suggest a more prominent role than previously appreciated for sequestered neutrophils in sepsis-induced lung inflammation.
Am J Respir Cell Mol Biol 1993 Feb
PMID:Activated pulmonary vascular neutrophils as early mediators of endotoxin-induced lung inflammation. 838 Dec 91

Previous analysis of plasmid DNA transfected into 108 cell clones demonstrated extensive polymorphism near the integration site in one clone. This polymorphism was apparent by Southern blot analysis as diffuse bands that extended over 30 kb. In the present study, nucleotide sequence analysis of cloned DNA from the integration site revealed telomere repeat sequences at the ends of the integrated plasmid DNA. The telomere repeat sequences at one end were located at the junction between the plasmid and cell DNA. The telomere repeat sequences at the other end were located in the opposite orientation in the polymorphic region and were shown by digestion with BAL 31 to be at the end of the chromosome. Telomere repeat sequences were not found at this location in the plasmid or parent cell DNA. Although the repeat sequences may have been acquired by recombination, a more likely explanation is that they were added to the ends of the plasmid by telomerase before integration. Comparison of the cell DNA before and after integration revealed that a chromosome break had occurred at the integration site, which was shown by fluorescent in situ hybridization to be located near the telomere of chromosome 13. These results demonstrate that chromosome breakage and rearrangement can result in interstitial telomere repeat sequences within the human genome. These sequences could promote genomic instability, because short repeat sequences can be recombinational hotspots. The results also show that DNA rearrangements involving telomere repeat sequences can be associated with chromosome breaks. The introduction of telomere repeat sequences at spontaneous or ionizing radiation-induced DNA strand breaks may therefore also be a mechanism of chromosome fragmentation.
Mol Cell Biol 1993 Feb
PMID:Acquisition of telomere repeat sequences by transfected DNA integrated at the site of a chromosome break. 842 17

The E-series prostaglandins (PGEs) are complex lipid regulators of B lymphocyte function. They inhibit the growth of certain B lymphoma lines. We report that heterogeneity with respect to PGE-induced growth inhibition correlates with the maturation state of the B cell lines. Specifically, the pre-B cell line 70Z/3 and the immature lymphoma CH31 are extremely sensitive to PGE2. To a lesser degree, other immature lymphomas (CH33, ECH408.1 and WEHI-231) are sensitive to PGE2. More mature lymphomas (BAL-17, CH12 and CH27) and fully differentiated myelomas (J558 and MOPC-315) are insensitive to PGE2. It is unknown what subtype of PGE receptor(s) (EPs) are expressed by B lymphocytes. It is also unknown if modulation of EP receptor expression could account for the differences in the sensitivity of these B cell lines to PGE2. To investigate these issues, reverse transcriptase polymerase chain reaction, Northern blot and DNA sequencing analyses were employed to obtain a definitive EP receptor subtype profile for these B cell lines, and for normal splenic B lymphocytes. Both normal and transformed B lymphocytes express mRNA encoding EP1, EP3beta and EP4 subtypes of PGE receptors. The B lineage cells do not express EP3alpha nor EP3gamma mRNA. The B cell lines are clonal, indicating that EP1, EP3beta and EP4 mRNA are coexpressed. Surprisingly, quantitative differences in basal EP1, EP3beta and EP4 expression were not observed between B cell lines despite their differing susceptibilities to PGE-induced growth inhibition. Conversely, the polyclonal activator LPS selectively upregulates EP4 mRNA expression in the mature B cell line CH12, but not in the LPS-sensitive pre-B cell line, 70Z/3. The activator LPS does not affect EP1 nor EP3beta mRNA expression. Treatment with dbcAMP, an analog of cAMP, mimics PGE-induced growth inhibition indicating that Gs-coupled EP2 and/or EP4 receptors mediate this inhibitory signal. Indeed, EP2 agonists mimic PGE2-induced growth inhibition unlike IP, EP1 and EP3-selective agonists. These data indicate that EP2 receptors are sufficient for mediating PGE-induced growth inhibition of susceptible B lineage cells.
Mol Immunol 1996 Jan
PMID:A molecular analysis of PGE receptor (EP) expression on normal and transformed B lymphocytes: coexpression of EP1, EP2, EP3beta and EP4. 860 22

Engagement of surface immunoglobulin on mature B cells leads to rescue from apoptosis and to proliferation. Levels of bcl-2 mRNA and protein increase with cross-linking of surface immunoglobulin. We have located the major positive regulatory region for control of bcl-2 expression in B cells in the 5'-flanking region. The positive region can be divided into an upstream and a downstream regulatory region. The downstream regulatory region contains a cyclic AMP-responsive element (CRE). We show by antibody supershift experiments and UV cross-linking followed by denaturing polyacrylamide gel electrophoresis that both CREB and ATF family members bind to this region in vitro. Mutations of the CRE site that result in loss of CREB binding also lead to loss of functional activity of the bcl-2 promoter in transient-transfection assays. The presence of an active CRE site in the bcl-2 promoter implies that the regulation of bcl-2 expression is linked to a signal transduction pathway in B cells. Treatment of the mature B-cell line BAL-17 with either anti-immunoglobulin M or phorbol 12-myristate 13-acetate leads to an increase in bcl-2 expression that is mediated by the CRE site. Treatment of the more immature B-cell line, Ramos, with phorbol esters rescues the cells from calcium-dependent apoptosis. bcl-2 expression is increased following phorbol ester treatment, and the increased expression is dependent on the CRE site. These stimuli result in phosphorylation of CREB at serine 133. The phosphorylation of CREB that results in activation is mediated by protein kinase C rather than by protein kinase A. Although the CRE site is necessary, optimal induction of bcl-2 expression requires participation of the upstream regulatory element, suggesting that phosphorylation of CREB alters its interaction with the upstream regulatory element. The CRE site in the bcl-2 promoter appears to play a major role in the induction of bcl-2 expression during the activation of mature B cells and during the rescue of immature B cells from apoptosis. It is possible that the CRE site is responsible for induction of bcl-2 expression in other cell types, particularly those in which protein kinase C is involved.
Mol Cell Biol 1996 Oct
PMID:Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis. 881 67

The stability of rat hepatic trihydroxycoprostanoyl-CoA syntethase was studied in its native membrane environment and after solubilisation by Triton X-100, and compared to that of choloyl-CoA synthetase. The lability of both delipidated enzymes could be suppressed by high concentrations of polyols such as sucrose and glucose. Addition of phospholipids to the assay mixtures was necessary to restore the activity of the stabilized enzymes. For further chromatographic separations, the addition of the hydrotrope Triton H-66 to the glucose-stabilized Triton X-100 solubilised synthetases improved their recovery on different matrices. Gel filtration revealed a native molecular mass of the Triton X-100/Triton H-66/protein micelles of 212 and 207 kDa for choloyl-CoA synthetase and trihydroxycoprostanoyl-CoA synthetase respectively.
Biochem Mol Biol Int 1996 Oct
PMID:Stabilisation and partial purification of Triton X-100 solubilised trihydroxycoprostanoyl-CoA synthetase from rat liver. 890 53

Eukaryotic telomeres are variable at several levels, from the length of the simple sequence telomeric repeat tract in different cell types to the presence or number of telomere-adjacent DNA sequence elements in different strains or individuals. We have investigated the sequence organization of Xenopus laevis telomeres by use of the vertebrate telomeric repeat (TTAGGG)n and blot hybridization analysis. The (TTAGGG)n-hybridizing fragments, which ranged from less than 10 to over 50 kb with frequently cutting enzymes, defined a pattern that was polymorphic between individuals. BAL 31 exonuclease treatment confirmed that these fragments were telomeric. The polymorphic fragments analyzed did not hybridize to 5S RNA sequences, which are telomeric according to in situ hybridization. When telomeric fragments from offspring (whole embryos) were compared to those from the spleens of the parents, the inheritance pattern of some bands was found to be unusual. Furthermore, in one cross, the telomeres of the embryo were shorter than the telomeres of the parents' spleen, and in another, the male's testis telomeres were shorter than those of the male's spleen. Our data are consistent with a model for chromosome behavior that involves a significant amount of DNA rearrangement at telomeres and suggest that length regulation of Xenopus telomeres is different from that observed for Mus spretus and human telomeres.
Mol Cell Biol 1998 Jan
PMID:Telomere variation in Xenopus laevis. 941 74

Phenylmercury acetate (PMA), which not only causes an elevation of sister chromatid exchanges (SCEs) but also induces high frequency of endoreduplication in human lymphocytes, may be genotoxic to humans. The major aim of our study was to investigate the effects of germanium oxide (GeO2), D-penicillamine (D-PA), dimercaprol (BAL), and diltiazem (DTM) on PMA-induced genotoxicity as quantified by SCEs. All concentrations of the four chemical compounds tested alone did not induce genotoxicity in cultured human lymphocytes. However, GeO2 significantly inhibited PMA-induced genotoxicity in a concentration-dependent manner. Similarly, D-PA at concentrations of 3 microM and 10 microM, and BAL at a concentration of 30 microM produced the antigenotoxic effects. In addition, GeO2 (1.5 microM) significantly reversed an increase of endoreduplication frequency caused by PMA. In a cell cycle kinetic study, GeO2 (0.5-5.0 microM) reversed the inhibition of PMA on the proliferating rate index (PRI) of lymphocytes. On the contrary, both D-PA and DTM at concentrations of 30-300 microM markedly potentiated PMA-induced inhibition of PRI. These findings show that GeO2, D-PA and BAL could antagonize PMA-induced genotoxicity, and GeO2 appears to be the most effective.
Environ Mol Mutagen 1998
PMID:Effects of germanium oxide and other chemical compounds on phenylmercury acetate-induced genotoxicity in cultured human lymphocytes. 954 93

Pulmonary sarcoidosis involves development of parenchymal granulomata that usually resolve spontaneously; however, it remains unclear what pathogenic mechanisms are responsible for the progression to local or diffuse fibrosis with irreversible lung remodeling that occurs in 20% of patients. Alveolar macrophages have a pivotal role in sarcoidosis, releasing mediators including insulin-like growth factor (IGF)-1, a potent profibrogenic molecule. IGF-1 bioavailability in the lung is dependent on at least six high-affinity IGF-binding proteins (IGFBP), which mainly inhibit IGF-1 action. We have investigated their presence in patients with established stage III sarcoidosis to determine whether IGF-1 and IGFBP contribute to the fibrogenic process in these patients and as such contribute to the (clinical) progression of the disease. The fibroblast mitogenic potential of bronchoalveolar lavage fluid (BALF) was more than 3-fold higher (P < 0.005) in sarcoid patients. Sarcoid BALF-induced activity could be inhibited (P < 0.0005) by neutralizing antibodies to IGF-1. We established the IGFBP profile of BALF with Western ligand analysis and quantified expression of IGFBP-3 by immunoblotting. IGFBP-2 and IGFBP-4 predominate in normal and sarcoid BALF, but IGFBP-3 occurs only as a modified, smaller, 29-kD form, expression of which was raised (P < 0.003) in sarcoid patients. Gene expression of IGF-1 and IGFBP-3 was demonstrated by reverse transcription-polymerase chain reaction in BAL cells. Thus, local production of pro-fibrogenic IGF-1 may be subject to substantial post-translational regulation by associated IGFBP and IGFBP proteases that may contribute to enhanced fibrogenesis in sarcoidosis patients with evidence of progression or (development) of fibrosis.
Am J Respir Cell Mol Biol 1998 Aug
PMID:Expression of insulin-like growth factor binding proteins in bronchoalveolar lavage fluid of patients with pulmonary sarcoidosis. 969 97

B cells stimulated by the combination of CD40L plus anti-Ig were screened for upregulated gene expression in an unbiased fashion through differential display. An inducible transcript was obtained that corresponds to a sequence previously isolated from pre-B cells and termed murine Sik-similar protein (mSSP). The mSSP gene is predominantly expressed in lymphoid tissues, including spleen and thymus, as well as testis, with lesser amounts in kidney and ovary. Among lymphocyte cell lines, mSSP expression varies widely. The mSSP protein is localized to the nucleus in NIH3T3 cells, and its expression in BAL-17 B cells varies with cell cycle progression. Expression of mSSP increased significantly within the first hours of B cell treatment with either CD40L, anti-IgM, or phorbol myristate acetate (PMA) with or without ionomycin. The predicted amino acid sequence of mSSP bears some homology to proteins involved in ribosomal RNA synthesis and processing. mSSP is a previously identified pre-B cell gene now shown for the first time to be an activation-responsive transcript in mature, primary B cells.
Mol Immunol 2002 Mar
PMID:B cell activation leads to upregulated expression of the murine Sik-similar protein gene. 1192 44


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