Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stimulation of granulocyte macrophage-colony stimulating factor (GM-CSF) by interleukin-1 (IL-1) has been shown to be counteracted in different mesenchymal cell systems by cyclic adenosine monophosphate (cAMP) agonists. The aim of this study was the evaluation of different cAMP agonists on GM-CSF expression in human bone marrow stromal cells. Incubation of secondary haematopoietic progenitor cell deprived human stromal cell cultures with IL-1 or TNF-alpha induced GM-CSF protein expression in culture supernatants and GM-CSF-mRNA in adherent stromal cells. The coincubation with 8-bromo-cAMP (8BrcAMP), a water soluble cAMP analogue, inhibited this GM-CSF stimulation at the protein and the mRNA level. This effect was dose dependent with a maximal inhibition of about 65% occurring at a 8BrcAMP concentration of 0.75 mM. In addition to 8BrcAMP, other cAMP agonists such as dibutyryl-cAMP, forskolin, pertussis toxin, or prostaglandin E2 (PGE2) had the same inhibitory effect on GM-CSF stimulation by IL-1. Coincubation with the cyclooxygenase inhibitor indomethacin had no significant influence on GM-CSF expression in stromal cells. Our results provide evidence that the previously described inhibitory effect of cAMP agonist PGE2 on haematopoietic progenitor cells in vivo is, at least in part, mediated by modulating the expression of GM-CSF in bone marrow stromal cells.
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PMID:cAMP analogues downregulate the expression of granulocyte macrophage colony-stimulating factor (GM-CSF) in human bone marrow stromal cells in vitro. 970 7

1. Antioxidants can exert protective effects in endotoxic shock by either a reduction of the oxidant damage or attenuation of Tumour Necrosis Factor (TNF-alpha) production. 2. Lazaroids are a family of compounds that inhibit lipid peroxidation. Besides, they can also reduce TNF-alpha. U-83836E is a new lazaroid lacking the glucocorticoid ring. 3. Aim of our study was to investigate the effect of U-83836E on TNF-alpha production either in vivo or in vitro. Endotoxic shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg kg(-1) of S. enteritidis lipopolysaccharide (LPS). LPS administration reduced survival rate (0% survival, 72 h after endotoxin administration), decreased mean arterial blood pressure, increased serum and macrophage TNF-alpha and enhanced plasma malonylaldehyde (MAL) levels. Furthermore aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE 1 nM-10 microM). 4. Treatment with U-83836E (7.5, 15 and 30 mg kg(-1), i.v.) 5 min after endotoxin challenge significantly protected against LPS induced lethality (90% survival rate and 80% survival rate 24 h and 72 h after LPS injection respectively, following the highest dose of the drug), reduced hypotension, blunted plasma MAL, decreased serum and macrophage TNF-alpha and restored the hyporeactivity of aortic rings to control values. In vitro LPS stimulation (50 microg ml(-1) for 4 h) significantly increased cytokine production in macrophages (Mphi) harvested from untreated normal rats. Pretreatment with pertussis toxin (PT; 0.1, 1 and 10 ng ml(-1) 4 h before LPS) significantly increased TNF-alpha production. PT effects on these LPS responses were correlated with a PT mediated ADP ribosylation of a 41 kDa protein. U-83836E (50 microM) reduced, in a dose dependent manner, LPS induced TNF-alpha production and inhibited the PT effects on cytokine production and on ADP ribosylation of the protein. 5. Our data suggest that lazaroids may affect the early events associated with LPS receptor mediated activation of a G protein in LPS induced TNF-alpha production. These molecular events may explain, at least in part, the in vivo inhibition of cytokine production and reversal of endotoxic shock.
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PMID:Inhibition of tumour necrosis factor and reversal of endotoxin-induced shock by U-83836E, a 'second generation' lazaroid in rats. 972 Aug 3

HIV replication and LTR-mediated gene expression can be modulated by CD8+ T cells in a cell type-dependent manner. We have previously shown that supernatants of activated CD8+ T cells of HIV-infected individuals greatly enhanced p24 levels in human macrophages infected with NSI or SI primary isolates of HIV-1. Here we have examined the effect of culture with CD8+ T cell supernatants on HIV-1 LTR-mediated gene expression in monocytic cells. CD8+ T cell supernatants enhanced LTR-mediated gene expression in U38 cells activated with Tat in the absence or presence of phorbol myristate acetate (PMA) and ionomycin or TNF-alpha. Further, enhancement of LTR-mediated gene expression and virus replication in U38 cells and U1 cells, respectively, was pertussis toxin-sensitive. The enhancement of gene expression and virus replication was associated with increased levels of TNF-alpha and was significantly abrogated by antibody to TNF-alpha. In contrast, the suppression of LTR-mediated gene expression by CD8+ T cell supernatants in Jurkat T cells was not pertussis toxin-sensitive and TNF-alpha levels were not affected. These results demonstrate that factors produced by CD8+ T cells utilize different cellular pathways to mediate their effects on HIV transcription and replication in different cell types.
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PMID:CD8+ T cell-mediated enhancement of tumour necrosis factor-alpha (TNF-alpha) production and HIV-1 LTR-driven gene expression in human monocytic cells is pertussis toxin-sensitive. 1036 Dec 38

The ability of CD8+ T lymphocytes to suppress the transcription and replication of HIV-1 is well documented. We have demonstrated that the factor(s) responsible for the suppression of HIV-1 LTR-mediated gene expression are not the CC chemokines RANTES, MIP-1alpha, and MIP-1beta. Interestingly, these and other chemokines and cytokines are produced by both CD8+ and CD4+ T lymphocytes. On the presumption that CD4+ T lymphocytes may also be able to modulate HIV-1 expression in vitro we assessed the LTR-modulatory effects of a panel of culture supernatants derived from stimulated CD4+ T lymphocytes from HIV-positive patients and uninfected controls. Supernatants of both CD4+ and CD8+ T cells mediated a suppression of LTR-driven gene expression in Jurkat T cells and an enhancement of gene expression in U38 monocytic cells. On the basis of these results, and using a herpesvirus saimiri (HVS)-transformed CD4+ T lymphocyte clone (HVSCD4), we demonstrate that both suppressive and enhancing effects are dose dependent. Furthermore, we have shown that supernatants of both HVSCD4 and HVSCD8 cells suppress LTR-mediated gene expression and HIV-1 replication in transfected/infected T cells. In U1 monocytic cells, supernatants of both CD4+ and CD8+ lymphocytes from an HIV-1-infected individual enhanced LTR-mediated gene expression, HIV-1 replication, and TNF-alpha production. However, only these effects as induced by CD8+ T cells were sensitive to the G protein inhibitor pertussis toxin. These results indicate that factors produced by both CD4+ and CD8+ T cells exert dichotomous effects on HIV-1 gene expression and replication in T cells and monocytes.
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PMID:T cell-derived suppressive activity: evidence of autocrine noncytolytic control of HIV type 1 transcription and replication. 1058 Apr 6

IL-12 plays a critical role in protective immunity against intracellular pathogens by promoting the development of Th1 cells. Here we demonstrate that filamentous hemagglutinin (FHA), a virulence factor of Bordetella pertussis, is capable of suppressing IL-12 production by macrophages. FHA inhibited IL-12 secretion by a macrophage cell line or ex vivo alveolar macrophages in response to Escherichia coli or B. pertussis lipopolysaccharide (LPS) and IFN-gamma. Antibodies to FHA or denaturation of FHA abrogated the inhibitory effect. Injection of mice with FHA suppressed IL-12 and IFN-gamma levels in the serum in response to i. v. injection of LPS in a model of septic shock. The suppressive effect of FHA was specific for IL-12, since the production of TNF-alpha, IL-6 and IL-10 was not suppressed, and production of IL-6 and IL-10 was up-regulated. Antibody blocking studies revealed that the inhibitory effect of FHA on IL-12 production was dependent on IL-10. Since FHA is secreted at high levels and local T cell responses are suppressed during B. pertussis infection, the findings suggest that FHA may be a critical virulence factor in facilitating pathogen persistence in the respiratory tract by suppressing or delaying the development of cell-mediated immunity.
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PMID:Direct anti-inflammatory effect of a bacterial virulence factor: IL-10-dependent suppression of IL-12 production by filamentous hemagglutinin from Bordetella pertussis. 1067 Nov 96

To elucidate the factor(s) accelerating the autoimmune disease processes, we induced two types of experimental autoimmune encephalomyelitis (EAE), severe and very mild, in F344 rats by immunization with myelin basic protein (MBP) plus pertussis toxin (PT) (PT+) or with MBP alone (PT-) and compared the differences between the two. Immunohistochemical examinations showed that although the nature of inflammation was essentially the same between the two groups, the proportion of Vbeta8.2(+) T cells in the CNS lesion of PT (+) rats was larger than that of PT (-) rats. Cytokine analysis by competitive PCR revealed that IL-10 mRNA in the lymphoid organ was significantly suppressed in the PT(+) group, whereas levels of IFN-gamma,TNF-alpha and TGF-beta mRNA were insignificantly different after PT administration. In addition, T cells taken from PT (+) rats proliferated well in response to MBP, while those from PT (-) rats showed a marginal response to the same antigen. However, this finding does not indicate the switching of non-encephalitogenic to encephalitogenic T cells upon PT administration because PT (-) rats contained encephalitogenic T cells and/or their precursor cells as revealed by adoptive transfer experiments. Taken together, these findings suggest that suppression of IL-10 by PT administration is the major factor contributing to the exacerbation of EAE in PT(+) rats.
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PMID:Analysis of experimental autoimmune encephalomyelitis induced in F344 rats by pertussis toxin administration. 1068 10

Leukocyte adhesion and trafficking at the endothelium requires both cellular adhesion molecules and chemotactic factors. A newly identified CX3C chemokine, fractalkine, expressed on activated endothelial cells, plays an important role in leukocyte adhesion and migration. We examined the functional effects of fractalkine on beta1 and beta2 integrin-mediated adhesion using a macrophage-like cell line, THP-1 cells. In this study, we report that THP-1 cells express mRNA encoding a receptor for fractalkine, CX3CR1, determined by Northern blotting. Scatchard analysis using fractalkine-SEAP (secreted form of placental alkaline phosphatase) chimeric proteins revealed that THP-1 cells express a single class of CX3CR1 with a dissociation constant of 30 pM and a mean expression of 440 sites per cell. THP-1 cells efficiently adhered, in a fractalkine-dependent manner, to full-length of fractalkine immobilized onto plastic and to the membrane-bound form of fractalkine expressed on ECV304 cells or TNF-alpha-activated HUVECs. Moreover, soluble-fractalkine enhanced adhesion of THP-1 cells to fibronectin and ICAM-1 in a dose-dependent manner. Pertussis toxin, an inhibitor of Gi, inhibited the fractalkine-mediated enhancement of THP-1 cell adhesion to fibronectin and ICAM-1. Finally, we found that soluble-fractalkine also enhanced adhesion of freshly separated monocytes to fibronectin and ICAM-1. These results indicate that fractalkine may induce firm adhesion between monocytes and endothelial cells not only through an intrinsic adhesion function itself, but also through activation of integrin avidity for their ligands.
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PMID:CX3C-chemokine, fractalkine-enhanced adhesion of THP-1 cells to endothelial cells through integrin-dependent and -independent mechanisms. 1075 31

We explored the role of Gi protein signaling in the regulation of interleukin (IL)-12 production and T helper cell type 1 (Th1) T cell differentiation. In initial studies, we showed that treatment of normal mice with pertussis toxin (PT), which inhibits Gi protein signaling, enhanced the capacity of splenocytes to produce IL-12 in response to both microbial and nonmicrobial stimuli. In addition, PT treatment increased the production of tumor necrosis factor (TNF)-alpha and IL-10 by stimulated cells. These findings were corroborated by the fact that untreated Gi2alpha(2/-) mice exhibited enhanced production of IL-12 and TNF-alpha by splenocytes, and of IL-12 p40 by purified spleen CD8alpha(+) lymphoid dendritic cells. Finally, we showed that while normal BALB/c mice infected with Leishmania major exhibited a nonhealing phenotype, those treated with PT when infection was initiated exhibited a healing phenotype along with an enhancement of leishmania-specific Th1 responses in draining lymph nodes. Further, healing was prevented by coadministration of anti-IL-12 and PT. These data demonstrate that endogenous Gi protein signaling has a primary role in the regulation of IL-12 production and the induction of Th1 responses in vivo.
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PMID:Primary role for Gi protein signaling in the regulation of interleukin 12 production and the induction of T helper cell type 1 responses. 1079 Apr 34

HIV-1 protein Tat is neurotoxic and increases macrophage and microglia production of TNF-alpha, a cytopathic cytokine linked to the neuropathogenesis of HIV dementia. Others have shown that intracellular calcium regulates TNF-alpha production in macrophages, and we have shown that Tat releases calcium from inositol 1,4, 5-trisphosphate (IP3) receptor-regulated stores in neurons and astrocytes. Accordingly, we tested the hypothesis that Tat-induced TNF-alpha production was dependent on the release of intracellular calcium from IP3-regulated calcium stores in primary macrophages. We found that Tat transiently and dose-dependently increased levels of intracellular calcium and that this increase was blocked by xestospongin C, pertussis toxin, and by phospholipase C and type 1 protein kinase C inhibitors but not by protein kinase A or phospholipase A2 inhibitors. Xestospongin C, BAPTA-AM, U73122, and bisindolylmalemide significantly inhibited Tat-induced TNF-alpha production. These results demonstrate that in macrophages, Tat-induced release of calcium from IP3-sensitive intracellular stores and activation of nonconventional PKC isoforms play an important role in Tat-induced TNF-alpha production.
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PMID:Release of calcium from inositol 1,4,5-trisphosphate receptor-regulated stores by HIV-1 Tat regulates TNF-alpha production in human macrophages. 1084 12

Endothelial cell adhesion molecules (CAMs) E-selectin, ICAM-1, and VCAM-1 play variably important roles in immune-mediated processes. They are induced by the proinflammatory cytokines IL-1 and TNF-alpha, and NF-kappaB is required for the regulated expression of all three genes. Regulators of this pathway could potentially be potent immune modulators. We studied the effect of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin, on cytokine-induced expression of CAMs in HUVEC. Unexpectedly, pretreatment with simvastatin potentiated the induction of all three endothelial CAMs by IL-1 and TNF, but not LPS or PMA, as detected by flow cytometry. Northern blot analysis demonstrated an increase in steady state IL-1-induced E-selectin mRNA levels in cells pretreated with simvastatin. This was associated with an increase in nuclear translocation of NF-kappaB, as detected by EMSA. The effect of simvastatin was reversed by mevalonate and geranylgeranyl pyrophosphate but not squalene, indicating that an inhibitory prenylated protein is involved in endothelial responses to proinflammatory cytokines. Pertussis toxin mimicked the effect of simvastatin, and the G protein activator NaF inhibited the cytokine-induced expression of endothelial CAMs, indicating that a Gialpha protein is involved. These results demonstrate that cytokine-mediated activation of the endothelium, and specifically CAM induction, can be modulated by a heterotrimeric G protein-coupled pathway. This may represent a "basal tone" of endothelial inactivation, which can either be disinhibited or amplified, depending on the stimulus.
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PMID:Simvastatin modulates cytokine-mediated endothelial cell adhesion molecule induction: involvement of an inhibitory G protein. 1094 2


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