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]
Citations
Cites
Cell Death: The Significance of Apoptosis
Wyllie, A. H., Kerr, J. F. R., & Currie, A. R. (1980) · International review of cytology · doi:10.1016/s0074-7696(08)62312-8 · Cited by 7,151
Cytokine-mediated regulation of CXCR4 expression in human neutrophils
Nagase, H., Miyamasu, M., Yamaguchi, M., Imanishi, M., Tsuno, N. H., Matsushima, K., Yamamoto, K., Morita, Y., & Hirai, K. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.71.4.711 · Cited by 4,713
de Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C. G., & de Vries, J. E. (1991) · The Journal of experimental medicine · doi:10.1084/jem.174.5.1209 · Cited by 3,762
Fadok, V. A., Voelker, D. R., Campbell, P. A., Cohen, J., Bratton, D. L., & Henson, P. M. (1992) · The Journal of Immunology · doi:10.4049/jimmunol.148.7.2207 · Cited by 3,321
Self-citationShull, M. M., Ormsby, I., Kier, A. B., Pawlowski, S., Diebold, R. J., Yin, M., Allen, R., Sidman, C., Proetzel, G., Calvin, D., et al. (1992) · Nature · doi:10.1038/359693a0 · Cited by 2,985
IL-10 inhibits cytokine production by activated macrophages
Fiorentino, D. F., Zlotnik, A., Mosmann, T. R., Howard, M., & O’Garra, A. (1991) · The Journal of Immunology · doi:10.4049/jimmunol.147.11.3815 · Cited by 2,888
Martin, S. J., Reutelingsperger, C. P., McGahon, A. J., Rader, J. A., van Schie, R. C., LaFace, D. M., & Green, D. R. (1995) · The Journal of experimental medicine · doi:10.1084/jem.182.5.1545 · Cited by 2,824
Koopman, G., Reutelingsperger, C. P. M., Kuijten, G., Keehnen, R. M. J., Pals, S. T., & van Oers, M. H. J. (1994) · Blood · doi:10.1182/blood.v84.5.1415.1415 · Cited by 2,687
Kulkarni, A. B., Huh, C. G., Becker, D., Geiser, A., Lyght, M., Flanders, K. C., Roberts, A. B., Sporn, M. B., Ward, J. M., & Karlsson, S. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.2.770 · Cited by 1,967
Savill, J. S., Wyllie, A. H., Henson, J. E., Walport, M. J., Henson, P. M., & Haslett, C. (1989) · Journal of Clinical Investigation · doi:10.1172/jci113970 · Cited by 1,536
Self-citationPhagocyte recognition of cells undergoing apoptosis
Savill, J., Fadok, V. A., Henson, P. M., & Haslett, C. (1993) · Immunology Today · doi:10.1016/0167-5699(93)90215-7 · Cited by 981
Self-citationVitronectin receptor-mediated phagocytosis of cells undergoing apoptosis
Savill, J., Dransfield, I., Hogg, N., & Haslett, C. (1990) · Nature · doi:10.1038/343170a0 · Cited by 846
Savill, J., Hogg, N., Ren, Y., & Haslett, C. (1992) · Journal of Clinical Investigation · doi:10.1172/jci116019 · Cited by 818
Haslett, C., Guthrie, L. A., Kopaniak, M. M., Johnston, R. B., & Henson, P. M. (1985) · PubMed Central · Cited by 779
Self-citationVerhoven, B. M., Schlegel, R., & Williamson, P. R. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.182.5.1597 · Cited by 669
Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression.
Kunkel, S. L., Spengler, M. L., May, M., Spengler, R. N., Larrick, J. W., & Remick, D. G. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)60727-6 · Cited by 661
Fadok, V. A., Savill, J., Haslett, C., Bratton, D. L., Doherty, D. E., Campbell, P. A., & Henson, P. M. (1992) · The Journal of Immunology · doi:10.4049/jimmunol.149.12.4029 · Cited by 596
Self-citationBogdan, C., Paik, J., Yoram Vodovotz, B., & Nathan, C. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)50091-0 · Cited by 502
Transforming growth factor beta: the good, the bad, and the ugly.
Wahl, S. M. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.180.5.1587 · Cited by 486
Macrophage recognition of cells undergoing programmed cell death (apoptosis).
Duvall, E., Wyllie, A. H., & Morris, R. G. (1985) · PubMed Central · Cited by 452
Homburg, C., de Haas, M., Borne, A. E. G. K. V. D., Verhoeven, A. J., Reutelingsperger, C. P. M., & Roos, D. (1995) · Blood · doi:10.1182/blood.v85.2.532.532 · Cited by 431
Platt, N., Suzuki, H., Kurihara, Y., Kodama, T., & Gordon, S. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.22.12456 · Cited by 428
Strassmann, G., Patil-koota, V., Finkelman, F. D., Fong, M., & Kambayashi, T. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.180.6.2365 · Cited by 364
Oswald, I. P., Wynn, T. A., Sher, A., & James, S. L. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.18.8676 · Cited by 353
Cox, G., Crossley, J., & Xing, Z. (1995) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.12.2.7865221 · Cited by 351
Neutrophil apoptosis is associated with a reduction in CD16 (Fc gamma RIII) expression.
Dransfield, I., Buckle, A., Savill, J., McDowall, A., Haslett, C., & Hogg, N. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.153.3.1254 · Cited by 329
Sambrano, G. R., & Steinberg, D. I. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.5.1396 · Cited by 294
Luciani, M., & Chimini, G. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00353.x · Cited by 289
Phagocytosis of apoptotic neutrophils does not induce macrophage release of thromboxane B2
MEAGHER, L. C., Savill, J., Baker, A. J., Fuller, R. W., & Haslett, C. (1992) · Journal of Leukocyte Biology · doi:10.1002/jlb.52.3.269 · Cited by 280
Stern, M., Savill, J., & Haslett, C. (1996) · Europe PMC (PubMed Central) · Cited by 239
Granulocyte apoptosis and the control of inflammation
Haslett, C., Savill, J., Whyte, M. K. B., Stern, M., Dransfield, I., & Meagher, L. (1994) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.1994.0113 · Cited by 228
Hormone-induced cell death. 2. Surface changes in thymocytes undergoing apoptosis.
Morris, R. G., Hargreaves, A. D., Duvall, E., & Wyllie, A. H. (1984) · PubMed Central · Cited by 202
Neutrophil apoptosis and clearance from neonatal lungs
Grigg, J., Silverman, M., Savill, J., Sarraf, C., & Haslett, C. (1991) · The Lancet · doi:10.1016/0140-6736(91)91443-x · Cited by 193
The clearance of apoptotic cells in the liver is mediated by the asialoglycoprotein receptor
Dini, L., Autuori, F., Lentini, A., Oliverio, S., & Piacentini, M. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)80373-o · Cited by 180
Mower, D. A., Peckham, D. W., Illera, V. A., Fishbaugh, J., Stunz, L. L., & Ashman, R. F. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.152.10.4832 · Cited by 151
SRB1, a Class B Scavenger Receptor, Recognizes both Negatively Charged Liposomes and Apoptotic Cells
Fukasawa, M., Adachi, H., Hirota, K., et al. (1996) · Experimental Cell Research · doi:10.1006/excr.1996.0030 · Cited by 141
Fadok, V. A., Laszlo, D. J., Noble, P. W., et al. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.151.8.4274 · Cited by 136
Self-citationMultiple systems for recognition of apoptotic lymphocytes by macrophages.
Pradhan, D., Krahling, S., Williamson, P., et al. (1997) · Molecular Biology of the Cell · doi:10.1091/mbc.8.5.767 · Cited by 128
Measurement by radioimmunoassay of prostaglandins as their methyl oximes
KELLY, R. W., Deam, S., Cameron, M., et al. (1986) · Prostaglandins Leukotrienes and Medicine · doi:10.1016/0262-1746(86)90201-5 · Cited by 124
Flora, P. K., & Gregory, C. D. (1994) · European Journal of Immunology · doi:10.1002/eji.1830241109 · Cited by 118
Pleiotropic Effects of Transforming Growth Factor‐β on Cells of the Immune System
Ruscetti, F. W., Varesio, L., Ochoa, A. C., & Ortaldo, J. R. (1993) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1993.tb35911.x · Cited by 84
Altered lipid packing identifies apoptotic thymocytes
Schlegel, R., STEVENS, M., Lumley-Sapanski, K., et al. (1993) · Immunology Letters · doi:10.1016/0165-2478(93)90101-7 · Cited by 79
IL-10 inhibits prostaglandin E2 production by lipopolysaccharide-stimulated monocytes
Niiro, H., Otsuka, T., Kuga, S., Nemoto, Y., Abe, M., Hara, N., Nakano, T., Ogo, T., & Niho, Y. (1994) · International Immunology · doi:10.1093/intimm/6.4.661 · Cited by 76
Enzyme Immunoassays of Icosanoids Using Acetylcholinesterase
Pradelles, P., Maclouf, J., & Grassi, J. J. (1985) · Springer eBooks · doi:10.1007/978-1-4684-7841-9_4 · Cited by 73
Measurement of peptidoleukotrienes in biological fluids
Westcott, J. Y., Johnston, K. P., Batt, R. A., et al. (1990) · Journal of Applied Physiology · doi:10.1152/jappl.1990.68.6.2640 · Cited by 71
Self-citation[3] Enzyme immunoassays of eicosanoids using acetylcholinesterase
Pradelles, P., Grassi, J. J., & Maclouf, J. (1990) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(90)87005-n · Cited by 67
Noble, P. W., Henson, P. M., Lucas, C., Mora-Worms, M., Carré, P. C., & Riches, D. W. H. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.151.2.979 · Cited by 59
Self-citationNiiro, H., Otsuka, T., Abe, M., Satoh, H., Ogo, T., NAKANO, T., Furukawa, Y., & Niho, Y. (1992) · PubMed · Cited by 39
Rotello, R. J., Fernandez, P.-A., & Yuan, J. (1994) · Development · doi:10.1242/dev.120.6.1421 · Cited by 30
Rose, D. M., Fadok, V. A., Riches, D. W. H., et al. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.12.5819 · Cited by 20
Self-citation
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Shapouri‐Moghaddam, A., Mohammadian, S., Vazini, H., Taghadosi, M., Esmaeili, S., Mardani, F., Seifi, B., Mohammadi, A., Afshari, J. T., & Sahebkar, A. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26429 · Cited by 4,930
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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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