Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Interferon-gamma Induced Gene Expression Changes in Human Neutrophils

ABSTRACT: The cytokine interferon-gamma (IFN-gamma) is used as a drug to treat Chronic Granulomatous Disease (CGD), a group of genetic disorders characterized by defects in components of the neutrophil-resident NADPH oxidase/Nox2 enzyme system. Administration of IFN-gamma to these patients results in decreased incidents of severe infection, but has no effect on the characteristic defect of CGD, the inability to convert oxygen to microbicidal reactive oxygen species. To determine the mechanism by which IFN-gamma enhances the host protective properties of neutrophils, we administered INF-gamma to 10 healthy adult volunteers and carried out transcription profiling by array for neutrophils isolated from their peripheral blood. IFN-gamma was administered to each subject at 4 doses (10, 25, 50 and 100 micrograms/meter squared) with washout periods between each dose. Gene expression levels in neutrophils were measure just before (time 0) and at various times (4, 8, 12, 24, 36, 48, 72 and 96 hours) after administration of IFN-gamma. In the list of samples, individual patients are indicated by 01-10, the dose by D10, D25, D50 and D100, referring to 10, 25, 50 and 100 micrograms / meter squared respectively and the times by visit (V) numbers where VI, V2, V3, V4, V5, V6, V7, V8 and V9 refer to the 0 4, 8, 12, 24, 36, 48, 72 and 96 hour time points respectively.

ORGANISM(S): Homo sapiens

SUBMITTER: Michael Ellison

PROVIDER: E-MTAB-7261 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Role of polyamines derived from arginine in differentiation and proliferation of human blood cells.

Maeda Tomoji T Wakasawa Takeru T Shima Yoichiro Y Tsuboi Isao I Aizawa Shin S Tamai Ikumi I

Biological & pharmaceutical bulletin 20060201 2

L-Arginine is a precursor of polyamine, nitric oxide (NO), creatine, and agmatine and is essential for the differentiation and proliferation of blood cells, although the precise biological role of L-arginine is unclear. We have recently reported that the depletion of L-arginine in cultured medium prevented both proliferation and differentiation of blood cells (Shima et al., Blood First Edition Paper, October 6, 2005; DOI 10.1182). Since one of metabolic products of L-arginine in the cells is pol ...[more]

PMID: 16462024

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Project description:Interferon-gamma (IFN-gamma) is approved as a drug to treat chronic granulomatous disease and osteopetrosis and is also used in hyperimmunoglobulin E syndromes. These primary immunodeficiencies involve defects in neutrophils/polymorphonuclear cells. Neutrophils mature in the bone marrow and then enter the blood where they quickly undergo apoptotic cell death with a half-life of 5-10 hours. Therefore we reasoned that IFN-gamma might exert its effects on neutrophils via prolonged exposure to cells undergoing maturation toward a terminally differentiated state in the marrow rather than by its brief exposure to short-lived circulating cells. To explore this possibility we made use of PLB-985 cells which are a myeloblast-like myeloid cell line that can be differentiated into a mature, neutrophil-like state by treatment with various agents including DMSO. In initial studies we investigated transcription and protein expression in PLB-985 cells undergoing DMSO-mediated maturation in the presence or absence of IFN-gamma and identified several classes of immunity related genes that were differentially expressed in the presence of the drug and could potentially explain the immune supportive properties of IFN-gamma. Next we explored if the effect of IFN-gamma on expression of these genes is dependent on whether the cells are undergoing maturation; to do this we compared the effects of IFN-gamma on cells cultured with and without DMSO. For a subset of genes the expression level changes caused by IFN-gamma were much greater in maturing cells than non-maturing cells. These findings indicate that developmental changes associated with cell maturation can modulate the effects of IFN-gamma and supports our hypothesis that the effects of the drug on developing neutrophils in the bone marrow may be very different from its effects on mature cells in the blood. We also compared the effects on gene expression of applying IFN-gamma either during DMSO mediated PLB-985 cell maturation or after maturation i.e. IFN-gamma was applied to already mature cells. For some genes we found that IFN-gamma applied to mature cells caused large changes in expression similar to those seen when IFN-gamma was applied during maturation, however for other genes no effect was seen when drug was applied to mature cells but large effects were seen when drug was applied during DMSO treatment. This data suggests that, in the former class of genes, the effects of IFN-gamma application during maturation are largely the result of the effects of the drug on cells approaching full maturity but in the latter class of genes the effects of IFN-gamma only become apparent when it is present throughout maturation. This further supports our hypothesis that the effects of IFN-gamma are modulated by developmental changes associated with cell maturation.

Dataset Information

Interferon-gamma Induced Gene Expression Changes in Human Neutrophils

Publications

Role of polyamines derived from arginine in differentiation and proliferation of human blood cells.

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