title: Phagocytosis of apoptotic cells by macrophages induces novel signaling events leading to cytokine-independent survival and inhibition of proliferation: activation of Akt and inhibition of extracellular signal-regulated kinases 1 and 2.
abstract: Recent evidence indicates that phagocytic clearance of apoptotic cells, initially thought to be a silent event, can modulate macrophage (M phi) function. We show in this work that phagocytic uptake of apoptotic cells or bodies, in the absence of serum or soluble survival factors, inhibits apoptosis and maintains viability of primary cultures of murine peritoneal and bone marrow M phi with a potency approaching that of serum-supplemented medium. Apoptotic uptake also profoundly inhibits the proliferation of bone marrow M phi stimulated to proliferate by M-CSF. While inhibition of proliferation is an unusual property for survival factors, the combination of increased survival and decreased proliferation may aid the M phi in its role as a scavenger during resolution of inflammation. The ability of apoptotic cells to promote survival and inhibit proliferation appears to be the result of simultaneous activation of Akt and inhibition of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1 and ERK2 (ERK1/2). While several activators of the innate immune system, or danger signals, also inhibit apoptosis and proliferation, danger signals and necrotic cells differ from apoptotic cells in that they activate, rather than inhibit, ERK1/2. These signaling differences may underlie the opposing tendencies of apoptotic cells and danger signals in promoting tolerance vs immunity.
authors.affiliation: Renal Section, Evans Memorial Department of Clinical Research, Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA.
authors.forename: Suman M
authors.initials: SM
authors.lastname: Reddy
authors.forename: K-H Kevin
authors.initials: KH
authors.lastname: Hsiao
authors.forename: Vivian Elizabeth
authors.initials: VE
authors.lastname: Abernethy
authors.forename: Hanli
authors.initials: H
authors.lastname: Fan
authors.forename: Angelika
authors.initials: A
authors.lastname: Longacre
authors.forename: Wilfred
authors.initials: W
authors.lastname: Lieberthal
authors.forename: Joyce
authors.initials: J
authors.lastname: Rauch
authors.forename: Jason S
authors.initials: JS
authors.lastname: Koh
authors.forename: Jerrold S
authors.initials: JS
authors.lastname: Levine
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001667:Binding, Competitive / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology*; D022162:Cytoplasmic Vesicles / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D005353:Fibronectins / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009336:Necrosis; D010587:Phagocytosis / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D003078:Colchicine; D016207:Cytokines; D005353:Fibronectins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019030:Receptors, Vitronectin; C494918:AKT1 protein, human