IL-12 Is Dysregulated in Macrophages from IRF-1 and IRF-2 Knockout Mice

Salkowski, Cindy A; Kopydlowski, Karen; Blanco, Jorge; Cody, M Joshua; McNally, Ranney; Vogel, Stefanie N

doi:10.4049/jimmunol.163.3.1529

Cited by 119interferon and immune responsesImmune Response and InflammationCytokine Signaling Pathways and Interactions

IL-12 Is Dysregulated in Macrophages from IRF-1 and IRF-2 Knockout Mice

Salkowski, Cindy A, Kopydlowski, Karen, Blanco, Jorge, Cody, M Joshua, McNally, Ranney, Vogel, Stefanie N·1999·The Journal of Immunology

DOI 10.4049/jimmunol.163.3.1529

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Abstract

Macrophages derived from IFN-regulatory factor-1 (IRF-1) and IRF-2 knockout (−/−) and wild-type (+/+) mice were utilized to examine the role of these transcription factors in the regulation of IL-12 mRNA and protein expression. Induction of IL-12 p40 mRNA by LPS was markedly diminished in both IRF-1−/− and IRF-2−/− macrophages. In contrast, IRF-1−/−, but not IRF-2−/−, macrophages exhibited impaired LPS-induced IL-12 p35 mRNA expression. The ability of IFN-γ to augment LPS-induced IL-12 p40 mRNA further when both stimuli were present simultaneously was significantly diminished in both IRF-1−/− and IRF-2−/− macrophages, with the most profound impairment observed for IRF-1−/− macrophages. Reductions in IL-12 mRNA expression after stimulation with LPS or LPS plus IFN-γ were accompanied by substantial reductions in IL-12 p40 and IL-12 p70 protein in both IRF-1−/− and IRF-2−/− macrophages. Priming IRF-1−/− and IRF-2−/− macrophages with IFN-γ for 24 h before LPS treatment partially restored impaired IL-12 mRNA and protein production in both IRF-1−/− and IRF-2−/− macrophages. Depressed IL-12 levels were paralleled by significant reductions in IFN-γ mRNA expression in IRF-1−/− and IRF-2−/− macrophages. These results indicate that both IRF-1 and IRF-2 are critical transcription factors in the regulation of macrophage IL-12 and consequently IFN-γ production.

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ICSBP alone is able to activate mouse and human IL-12 p40 promoters, acting through the Ets site, and exogenous IRF-1 synergizes with ICSBP.
“It was shown that ICSBP alone is able to activate mouse and human IL-12 p40 promoters.”
From Review: ICSBP/IRF-8: Its Regulatory Roles in the Development of Myeloid Cells (2002) · cites this paper as [46]

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Authors: Salkowski, C. A., Kopydlowski, K., Blanco, J., Cody, M. J., McNally, R., & Vogel, S. N.
Affiliations: Uniformed Services University of the Health Sciences (US)
ORCID: Blanco, Jorge
Vogel, Stefanie N
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 1999-08-01
Volume: 163
Issue: 3
Pages: 1529-1536
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.163.3.1529
OpenAlex: W4313347785
Cited by: 119
References: 66
Citations by year: 2025: 2 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 7 · 2012: 6
FWCI: 2.72
Type: journal article
Language: en
Open access: closed
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed
Topics: Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords: IL-12, IRF1, IRF2, macrophages, transcription factors, IL-12p40, IL-12p35, IL-12p70, interferon-gamma, LPS, gene expression regulation, knockout mice
MeSH terms: Interferon Regulatory Factor-8, Animals, DNA-Binding Proteins, Interferon-gamma, Lipopolysaccharides, Mice, Inbred C57BL, Phosphoproteins, Repressor Proteins, RNA, Messenger, Staphylococcus aureus, Transcription Factors, Zymosan, Up-Regulation, Consensus Sequence, Macrophages, Peritoneal, Mice, Knockout, Interleukin-12, Interferon Regulatory Factors, Interferon Regulatory Factor-2, Interferon Regulatory Factor-1, Mice

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IL-12 Is Dysregulated in Macrophages from IRF-1 and IRF-2 Knockout Mice

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