Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: Regulatory role in the innate immune response
Open accessAbstract
The importance of the macrophage in innate immunity is underscored by its secretion of an array of powerful immunoregulatory and effector molecules. We report herein that macrophage migration inhibitory factor (MIF), a product of activated macrophages, sustains macrophage survival and function by suppressing activation-induced, p53-dependent apoptosis. Endotoxin administration to MIF −/− mice results in decreased macrophage viability, decreased proinflammatory function, and increased apoptosis when compared with wild-type controls. Moreover, inhibition of p53 in endotoxin-treated, MIF-deficient macrophages suppresses enhanced apoptosis and restores proinflammatory function. MIF inhibits p53 activity in macrophages via an autocrine regulatory pathway, resulting in a decrease in cellular p53 accumulation and subsequent function. Inhibition of p53 by MIF coincides with the induction of arachidonic acid metabolism and cyclooxygenase-2 (Cox-2) expression, which is required for MIF regulation of p53. MIF's effect on macrophage viability and survival provides a previously unrecognized mechanism to explain its critical proinflammatory action in conditions such as sepsis, and suggests new approaches for the modulation of innate immune responses.
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In monocytes, heterodimers between CXCR2 and CD74 or between CXCR4 and CD74 induce PI3K-AKT signaling and p53 inhibition, leading to increased survival, proliferation and apoptosis evasion.
“In monocytes, heterodimers between CXCR2 and CD74 or between CXCR4 and CD74 induce PI3K-AKT signaling and p53 inhibition, leading to increased survival, proliferation and apoptosis evasion 22 .”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [22]
The Results and Discussion (page not provided) support MIF-mediated p53 inhibition and reduced apoptosis in mouse macrophages. They describe a Cox-2/PGE2 mechanism, not CXCR2–CD74 or CXCR4–CD74 heterodimers or PI3K–AKT signaling; they also do not establish increased monocyte proliferation. (LLM, conf=0.88)
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- Authors
- Mitchell, R. A., Liao, H., Chesney, J., Fingerle-Rowson, G., Baugh, J., David, J., & Bucala, R.
- Affiliations
- Picower Institute for Medical Research, New York, NY 11030; and Harvard School of Public Health, Boston, MA 02115
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-12-26
- Volume
- 99
- Issue
- 1
- Pages
- 345-350
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC117563
- OpenAlex
- W2087968772
- Cited by
- 622
- References
- 1
- Citations by year
- 2026: 17 · 2025: 19 · 2024: 19 · 2023: 25 · 2022: 17 · 2021: 25 · 2020: 21 · 2019: 24 · 2018: 20 · 2017: 29 · 2016: 30 · 2015: 21 · 2014: 30 · 2013: 32 · 2012: 35
- FWCI
- 5.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (1 R01 AI 42310-03, R01AI042310)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- macrophage migration inhibitory factor, p53, macrophage apoptosis, macrophage survival, innate immunity, endotoxin, cyclooxygenase-2, arachidonic acid metabolism, autocrine regulation, sepsis
- MeSH terms
- Animals, Cell Survival, Endotoxins, Enzyme-Linked Immunosorbent Assay, Genes, Dominant, Isoenzymes, Luciferases, Macrophage Migration-Inhibitory Factors, Macrophages, Male, Mice, Transgenic, Plasmids, Prostaglandin-Endoperoxide Synthases, Recombinant Fusion Proteins, Transfection, Tumor Necrosis Factor-alpha, Blotting, Western, Dinoprostone, Tumor Suppressor Protein p53, Arachidonic Acid, Apoptosis, Mice, Cyclooxygenase 2
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