The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.
Open accessAbstract
Apoptosis in vivo is followed almost inevitably by rapid uptake into adjacent phagocytic cells, a critical process in tissue remodeling, regulation of the immune response, or resolution of inflammation. Phagocytosis of apoptotic cells by macrophages has been suggested to be a quiet process that does not lead to production of inflammatory mediators. Here we show that phagocytosis of apoptotic neutrophils (in contrast to immunoglobulin G-opsonized apoptotic cells) actively inhibited the production of interleukin (IL)-1beta, IL-8, IL-10, granulocyte macrophage colony-stimulating factor, and tumor necrosis factor-alpha, as well as leukotriene C4 and thromboxane B2, by human monocyte-derived macrophages. In contrast, production of transforming growth factor (TGF)-beta1, prostaglandin E2, and platelet-activating factor (PAF) was increased. The latter appeared to be involved in the inhibition of proinflammatory cytokine production because addition of exogenous TGF-beta1, prostaglandin E2, or PAF resulted in inhibition of lipopolysaccharide-stimulated cytokine production. Furthermore, anti-TGF-beta antibody, indomethacin, or PAF receptor antagonists restored cytokine production in lipopolysaccharide-stimulated macrophages that had phagocytosed apoptotic cells. These results suggest that binding and/or phagocytosis of apoptotic cells induces active antiinflammatory or suppressive properties in human macrophages. Therefore, it is likely that resolution of inflammation depends not only on the removal of apoptotic cells but on active suppression of inflammatory mediator production. Disorders in either could result in chronic inflammatory diseases.
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“Some of the more common cytokines used in biomaterial‐based research involves the proinflammatory IFN‐γ or IL‐4, which are important effectors in steering the macrophage phenotypes.[ 103 , 232 , 233 , 234 ]”
From Unraveling and Harnessing the Immune Response at the Cell–Biomaterial Interface for Tissue Engineering Purposes (2024) · cites this paper as [234]
In the citing paper
“Interestingly, phagocytosis of neutrophils is also a central element to induce the phenotype switch of macrophages from pro-inflammatory M1 to a reparative M2 phenotype [73].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [73]
In the citing paper
“2-AG increases the number of phagocytosing macrophages, which leads to increased production of anti-inflammatory cytokines, e.g., TGF-β1 and decreased output of pro-inflammatory cytokines, e.g., TNF-α by macrophages [73].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [73]
In the citing paper
“Their apoptosis and engulfment by macrophages (efferocytosis) provides a key signal to the local immune milieu, including macrophages, to transition to an anti-inflammatory, pro-repair state”
From Immunology of Wound Healing (2018) · cites this paper as [47]
In the citing paper
“In physiologic wound repair, neutrophils undergo apoptosis after carrying out their various functions at the site of injury. Local macrophage uptake of apoptotic neutrophils then triggers a transition out of inflammatory phase [47–49].”
From Immunology of Wound Healing (2018) · cites this paper as [47]
In the citing paper
“Macrophages in the wound site are responsible for phagocytosis of apoptotic neutrophils, a process known as efferocytosis [73••]. This action itself induces macrophages to transition from a pro-inflammatory phenotype, to an anti-inflammatory phenotype”
From Immunology of Wound Healing (2018) · cites this paper as [47]
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“After engulfment of apoptotic cells, monocytes/macrophages (M ) release antiinflammatory cytokines, such as IL-10 and TGF- (2).”
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“In general, the engulfment of an apoptotic cell can induce an immunologically quiescent anti-inflammatory state of the postefferocytosis innate immune cell, with inhibition of the expression of pro-inflammatory cytokines, and at times also with the release of immunosuppressive cytokines, such as TGF-β [47–49].”
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“We showed here that homozygous deletion of hematopoietic DNMT3A led to fibrous cap thinning and impaired efferocytosis, two features of unstable plaques in humans that we predicted would occur via the suppression of TGF β 1 synthesis 9,19,20 .”
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“5,6 Along this phenotype switch, a proinflammatory mediator profile (eg, tumor necrosis factor- [TNF- ] or nitric oxide) changes to an immunosuppressive one, characterized by, for example, interleukin-10 (IL-10), transforming growth- 1 (TGF1), or prostaglandin E2.(7-9) Recent studies showed protection from apoptosis i…”
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“RT induces increased levels of suppressive factors including nitric oxide synthase (NOS) and reactive nitrogen intermediates (RNI), reactive oxygen species (ROS), cytokines (IL-4, IL-10, TGF-β), matrix metalloproteinases (MMPs), arginase I, collagenase, lipoxygenase (LOX) which in turn leads to the suppression of the…”
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“According to previous studies ( 17 , 31 ), apoptotic cells can convert the phenotype of macrophages to achieve the resolution of inflammation after clearance by macro phages, which promotes the transition from the inflammation stage to the stage of tissue repair and regeneration.”
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“To attenuate the release of autocrine mediators, macrophages were pre-incubated for 1 h with either fludarabine, a specific inhibitor of STAT1 (Frank et al., 1999), or STA-21, a specific STAT3 inhibitor (Song et al., 2005), prior to addition of AC-CM.”
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The Combination of Apoptotic U937 Cells and Lupus IgG Is a Potent IFN-α Inducer
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Metadata
- Authors
- Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., & Henson, P. M.
- Affiliations
- National Jewish Health (US)
- ORCID
- Henson, P M
- Venue
- Journal of Clinical Investigation
- Published
- 1998-02-15
- Volume
- 101
- Issue
- 4
- Pages
- 890-898
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508637
- OpenAlex
- W2095537212
- Semantic Scholar
- 3e88d8a52759097d481b92ec0d06606afbadafab
- Cited by
- 3,166
- References
- 50
- Citations by year
- 2026: 60 · 2025: 74 · 2024: 91 · 2023: 82 · 2022: 91 · 2021: 129 · 2020: 114 · 2019: 125 · 2018: 106 · 2017: 113 · 2016: 117 · 2015: 109 · 2014: 116 · 2013: 130 · 2012: 133
- FWCI
- 29.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL34303, P01HL034303)
- National Institute of General Medical Sciences (GM48211, R01GM048211)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- phagocytosis of apoptotic cells, macrophages, inflammation resolution, anti-inflammatory macrophages, inflammatory cytokines, TGF-β1, prostaglandin E2, platelet-activating factor, autocrine and paracrine signaling, neutrophil apoptosis, monocyte-derived macrophages, indomethacin, PAF receptor antagonists
- MeSH terms
- Humans, Inflammation, Macrophages, Neutrophils, Phagocytosis, Platelet Activating Factor, Solubility, Thromboxane B2, Dinoprostone, Cytokines, Transforming Growth Factor beta, Apoptosis, Leukotriene C4, Jurkat Cells
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