Identification of IRF-8 and IRF-1 target genes in activated macrophages

Natalie Dror; Michal Alter-Koltunoff; Aviva Azriel; Ninette Amariglio; Jasmine Jacob-Hirsch; Sharon Zeligson; Avigail Morgenstern; Tomohiko Tamura; Hansjörg Hauser; Gideon Rechavi; Keiko Ozato; Ben Zion Levi

doi:10.1016/j.molimm.2006.02.026

Identification of IRF-8 and IRF-1 target genes in activated macrophages

Natalie Dror, Michal Alter-Koltunoff, Aviva Azriel, Ninette Amariglio, Jasmine Jacob-Hirsch, Sharon Zeligson, Avigail Morgenstern, Tomohiko Tamura, Hansjörg Hauser, Gideon Rechavi, Keiko Ozato, Ben Zion Levi

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

Interferon regulatory factor 1 (IRF-1) and IRF-8, also known as interferon consensus sequence binding protein (ICSBP), are important regulators of macrophage differentiation and function. These factors exert their activities through the formation of heterocomplexes. As such, they are coactivators of various interferon-inducible genes in macrophages. To gain better insights into the involvement of these two transcription factors in the onset of the innate immune response and to identify their regulatory network in activated macrophages, DNA microarray was employed. Changes in the expression profile were analyzed in peritoneal macrophages from wild type mice and compared to IRF-1 and IRF-8 null mice, before and following 4 h exposure to IFN-γ and LPS. The expression pattern of 265 genes was significantly changed (up/down) in peritoneal macrophages extracted from wild type mice following treatment with IFN-γ and LPS, while no changes in the expression levels of these genes were observed in samples of the same cell-type from both IRF-1 and IRF-8 null mice. Among these putative target genes, numerous genes are involved in macrophage activity during inflammation. The expression profile of 10 of them was further examined by quantitative RT-PCR. In addition, the promoter regions of three of the identified genes were analyzed by reporter gene assay for the ability to respond to IRF-1 and IRF-8. Together, our results suggest that both IRF-1 and IRF-8 are involved in the transcriptional regulation of these genes. We therefore suggest a broader role for IRF-1 and IRF-8 in macrophages differentiation and maturation, being important inflammatory mediators.

Original language	English
Pages (from-to)	338-346
Number of pages	9
Journal	Molecular Immunology
Volume	44
Issue number	4
DOIs	https://doi.org/10.1016/j.molimm.2006.02.026
State	Published - Jan 2007
Externally published	Yes

Bibliographical note

Funding Information:
We are grateful to the Arison family donation to the center of DNA Chips, Pediatric Oncology, Chaim Sheba Medical Center and to Prof. Rubinstein from the Weizmann Institute for the generous gift of IRF-1 −/− mice. We thank Dr. Naama Rave-Harel from our laboratory for critical reading of the manuscript, and Dr. Shifra Ben-Dor from the Weizmann Institute for valuable help in data analysis. GR holds the Djerassi Chair in Oncology at the Sackler School of Medicine, and B.Z. Levi is an incumbent of the Lily and Silvian Marcus Chair in Life Sciences at the Technion. This research was partially funded by The Israel Science Foundation (Grant Number: 536/01), by the Center for the Study of Emerging Diseases (CSED), and the fund for the promotion of research at the Technion.

Keywords

CXCL16
H28
ICSBP
IRF-1
IRF-8
Interferon regulatory factors (IRFs)
LIF
MAP4K4
MMP9
MYC
Macrophage activation
PCDH7
PML
SOCS7
Transcriptional regulation

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10.1016/j.molimm.2006.02.026

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@article{c6268e019ac94175961b437b71436efd,

title = "Identification of IRF-8 and IRF-1 target genes in activated macrophages",

abstract = "Interferon regulatory factor 1 (IRF-1) and IRF-8, also known as interferon consensus sequence binding protein (ICSBP), are important regulators of macrophage differentiation and function. These factors exert their activities through the formation of heterocomplexes. As such, they are coactivators of various interferon-inducible genes in macrophages. To gain better insights into the involvement of these two transcription factors in the onset of the innate immune response and to identify their regulatory network in activated macrophages, DNA microarray was employed. Changes in the expression profile were analyzed in peritoneal macrophages from wild type mice and compared to IRF-1 and IRF-8 null mice, before and following 4 h exposure to IFN-γ and LPS. The expression pattern of 265 genes was significantly changed (up/down) in peritoneal macrophages extracted from wild type mice following treatment with IFN-γ and LPS, while no changes in the expression levels of these genes were observed in samples of the same cell-type from both IRF-1 and IRF-8 null mice. Among these putative target genes, numerous genes are involved in macrophage activity during inflammation. The expression profile of 10 of them was further examined by quantitative RT-PCR. In addition, the promoter regions of three of the identified genes were analyzed by reporter gene assay for the ability to respond to IRF-1 and IRF-8. Together, our results suggest that both IRF-1 and IRF-8 are involved in the transcriptional regulation of these genes. We therefore suggest a broader role for IRF-1 and IRF-8 in macrophages differentiation and maturation, being important inflammatory mediators.",

keywords = "CXCL16, H28, ICSBP, IRF-1, IRF-8, Interferon regulatory factors (IRFs), LIF, MAP4K4, MMP9, MYC, Macrophage activation, PCDH7, PML, SOCS7, Transcriptional regulation",

author = "Natalie Dror and Michal Alter-Koltunoff and Aviva Azriel and Ninette Amariglio and Jasmine Jacob-Hirsch and Sharon Zeligson and Avigail Morgenstern and Tomohiko Tamura and Hansj{\"o}rg Hauser and Gideon Rechavi and Keiko Ozato and Levi, {Ben Zion}",

note = "Funding Information: We are grateful to the Arison family donation to the center of DNA Chips, Pediatric Oncology, Chaim Sheba Medical Center and to Prof. Rubinstein from the Weizmann Institute for the generous gift of IRF-1 −/− mice. We thank Dr. Naama Rave-Harel from our laboratory for critical reading of the manuscript, and Dr. Shifra Ben-Dor from the Weizmann Institute for valuable help in data analysis. GR holds the Djerassi Chair in Oncology at the Sackler School of Medicine, and B.Z. Levi is an incumbent of the Lily and Silvian Marcus Chair in Life Sciences at the Technion. This research was partially funded by The Israel Science Foundation (Grant Number: 536/01), by the Center for the Study of Emerging Diseases (CSED), and the fund for the promotion of research at the Technion.",

year = "2007",

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doi = "10.1016/j.molimm.2006.02.026",

language = "אנגלית",

volume = "44",

pages = "338--346",

journal = "Molecular Immunology",

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T1 - Identification of IRF-8 and IRF-1 target genes in activated macrophages

AU - Dror, Natalie

AU - Alter-Koltunoff, Michal

AU - Azriel, Aviva

AU - Amariglio, Ninette

AU - Jacob-Hirsch, Jasmine

AU - Zeligson, Sharon

AU - Morgenstern, Avigail

AU - Tamura, Tomohiko

AU - Hauser, Hansjörg

AU - Rechavi, Gideon

AU - Ozato, Keiko

AU - Levi, Ben Zion

N1 - Funding Information: We are grateful to the Arison family donation to the center of DNA Chips, Pediatric Oncology, Chaim Sheba Medical Center and to Prof. Rubinstein from the Weizmann Institute for the generous gift of IRF-1 −/− mice. We thank Dr. Naama Rave-Harel from our laboratory for critical reading of the manuscript, and Dr. Shifra Ben-Dor from the Weizmann Institute for valuable help in data analysis. GR holds the Djerassi Chair in Oncology at the Sackler School of Medicine, and B.Z. Levi is an incumbent of the Lily and Silvian Marcus Chair in Life Sciences at the Technion. This research was partially funded by The Israel Science Foundation (Grant Number: 536/01), by the Center for the Study of Emerging Diseases (CSED), and the fund for the promotion of research at the Technion.

PY - 2007/1

Y1 - 2007/1

N2 - Interferon regulatory factor 1 (IRF-1) and IRF-8, also known as interferon consensus sequence binding protein (ICSBP), are important regulators of macrophage differentiation and function. These factors exert their activities through the formation of heterocomplexes. As such, they are coactivators of various interferon-inducible genes in macrophages. To gain better insights into the involvement of these two transcription factors in the onset of the innate immune response and to identify their regulatory network in activated macrophages, DNA microarray was employed. Changes in the expression profile were analyzed in peritoneal macrophages from wild type mice and compared to IRF-1 and IRF-8 null mice, before and following 4 h exposure to IFN-γ and LPS. The expression pattern of 265 genes was significantly changed (up/down) in peritoneal macrophages extracted from wild type mice following treatment with IFN-γ and LPS, while no changes in the expression levels of these genes were observed in samples of the same cell-type from both IRF-1 and IRF-8 null mice. Among these putative target genes, numerous genes are involved in macrophage activity during inflammation. The expression profile of 10 of them was further examined by quantitative RT-PCR. In addition, the promoter regions of three of the identified genes were analyzed by reporter gene assay for the ability to respond to IRF-1 and IRF-8. Together, our results suggest that both IRF-1 and IRF-8 are involved in the transcriptional regulation of these genes. We therefore suggest a broader role for IRF-1 and IRF-8 in macrophages differentiation and maturation, being important inflammatory mediators.

AB - Interferon regulatory factor 1 (IRF-1) and IRF-8, also known as interferon consensus sequence binding protein (ICSBP), are important regulators of macrophage differentiation and function. These factors exert their activities through the formation of heterocomplexes. As such, they are coactivators of various interferon-inducible genes in macrophages. To gain better insights into the involvement of these two transcription factors in the onset of the innate immune response and to identify their regulatory network in activated macrophages, DNA microarray was employed. Changes in the expression profile were analyzed in peritoneal macrophages from wild type mice and compared to IRF-1 and IRF-8 null mice, before and following 4 h exposure to IFN-γ and LPS. The expression pattern of 265 genes was significantly changed (up/down) in peritoneal macrophages extracted from wild type mice following treatment with IFN-γ and LPS, while no changes in the expression levels of these genes were observed in samples of the same cell-type from both IRF-1 and IRF-8 null mice. Among these putative target genes, numerous genes are involved in macrophage activity during inflammation. The expression profile of 10 of them was further examined by quantitative RT-PCR. In addition, the promoter regions of three of the identified genes were analyzed by reporter gene assay for the ability to respond to IRF-1 and IRF-8. Together, our results suggest that both IRF-1 and IRF-8 are involved in the transcriptional regulation of these genes. We therefore suggest a broader role for IRF-1 and IRF-8 in macrophages differentiation and maturation, being important inflammatory mediators.

KW - CXCL16

KW - H28

KW - ICSBP

KW - IRF-1

KW - IRF-8

KW - Interferon regulatory factors (IRFs)

KW - LIF

KW - MAP4K4

KW - MMP9

KW - MYC

KW - Macrophage activation

KW - PCDH7

KW - PML

KW - SOCS7

KW - Transcriptional regulation

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VL - 44

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EP - 346

JO - Molecular Immunology

JF - Molecular Immunology

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ER -

Identification of IRF-8 and IRF-1 target genes in activated macrophages

Abstract

Bibliographical note

Keywords

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