Cited by 3,166Phagocytosis and Immune RegulationImmune Response and InflammationImmune cells in cancer

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Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.

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Fadok, V A, Bratton, D L, Konowal, A, Freed, P W, Westcott, J Y, Henson, P M·1998·Journal of Clinical Investigation

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Abstract

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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Cyclic AMP Regulation of Neutrophil Apoptosis Occurs via a Novel Protein Kinase A-independent Signaling Pathway
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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
Publisher: American Society for Clinical Investigation
Published: 1998-02-15
Volume: 101
Issue: 4
Pages: 890-898
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci1112
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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Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.

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