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

Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print Cited Medium: Print ISSN: 0021-9738 (Print) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE

Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.

Apoptosis*; Cytokines/*immunology ; Dinoprostone/*immunology ; Macrophages/*immunology ; Neutrophils/*immunology ; Phagocytosis/*immunology ; Platelet Activating Factor/*immunology ; Transforming Growth Factor beta/*immunology; Cytokines/biosynthesis ; Cytokines/genetics ; Dinoprostone/biosynthesis ; Dinoprostone/metabolism ; Dinoprostone/pharmacology ; Humans ; Inflammation/immunology ; Jurkat Cells ; Leukotriene C4/metabolism ; Neutrophils/radiation effects ; Platelet Activating Factor/biosynthesis ; Platelet Activating Factor/metabolism ; Platelet Activating Factor/pharmacology ; Solubility ; Thromboxane B2/metabolism ; Transforming Growth Factor beta/biosynthesis ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta/pharmacology

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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GM-48211 United States GM NIGMS NIH HHS; HL-34303 United States HL NHLBI NIH HHS

0 (Cytokines)
0 (Platelet Activating Factor)
0 (Transforming Growth Factor beta)
2CU6TT9V48 (Leukotriene C4)
54397-85-2 (Thromboxane B2)
K7Q1JQR04M (Dinoprostone)

Date Created: 19980321 Date Completed: 19980317 Latest Revision: 20220330

20221213

PMC508637

10.1172/JCI1112

9466984