Dataset Information

Deciphering of the human interferome and its kinetics of protein induction and repression by mass spectrometry-based quantitative proteome analysis

ABSTRACT: Interferons (IFNs) are pleotropic cytokines secreted upon encounter of pathogens and tumors. Applying their antipathogenic, antiproliferative and immune stimulatory capacities, recombinant IFNs are frequently prescribed as drugs to treat different diseases. IFNs act by changing the transcription of cells. Due to characteristics like rapid induction and signaling, IFNs represent prototypic model systems for various aspects of biomedical research. In respect to the signaling and activated promoters, IFNs can be subdivided in two groups. Here, alterations of the cellular proteome of human cells treated with IFN and IFN were elucidated in a time-dependent manner by mass spectrometry-based quantitative proteome analysis. The majority of protein regulations were strongly IFN type- and time-dependent. In addition to the expected upregulation of IFN-induced proteins, an astonishing number of proteins become profoundly repressed especially by IFN. Taken together, our comprehensive analysis deciphers the human interferome and its kinetics of protein induction and repression.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

SUBMITTER: Dominik Andre Meger

LAB HEAD: Dominik Andre Megger

PROVIDER: PXD006442 | Pride | 2018-05-25

REPOSITORIES: Pride

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Deciphering of the Human Interferon-Regulated Proteome by Mass Spectrometry-Based Quantitative Analysis Reveals Extent and Dynamics of Protein Induction and Repression.

Megger Dominik A DA Philipp Jos J Le-Trilling Vu Thuy Khanh VTK Sitek Barbara B Trilling Mirko M

Frontiers in immunology 20170914

Interferons (IFNs) are pleotropic cytokines secreted upon encounter of pathogens and tumors. Applying their antipathogenic, antiproliferative, and immune stimulatory capacities, recombinant IFNs are frequently prescribed as drugs to treat different diseases. IFNs act by changing the gene expression profile of cells. Due to characteristics such as rapid gene induction and signaling, IFNs also represent prototypical model systems for various aspects of biomedical research (e.g., signal transductio ...[more]

PMID: 28959263

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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.

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