title: Ceramide inhibits IgG-dependent phagocytosis in human polymorphonuclear leukocytes.
abstract: Ceramide is a product of agonist-induced sphingolipid metabolism in several cell types, including polymorphonuclear leukocytes (PMNs). In adherent PMNs, the kinetics of ceramide production correspond with the termination of fMLP-stimulated H2O2 release. Furthermore, short chain ceramides inhibit fMLP-mediated H2O2 release in adherent PMNs. In the present study, we investigated the effects of short chain ceramides and sphingoid bases on phagocytosis of IgG-opsonized erythrocytes (EIgG) by suspended PMNs activated with fMLP. N-Acetylsphingosine, N-acetylphytosphingosine, phytosphingosine, sphingosine, and dihydrosphingosine, but not N-acetyldihydrosphingosine, inhibited phagocytosis of EIgG. In contrast, these same lipids did not inhibit fMLP-mediated chemotaxis. Endogenous ceramide levels increased within the first few minutes of phagocytosis, with a significant (P < .05) accumulation by 30 minutes, the time by which phagocytosis was terminated. Neutral sphingomyelinase activity paralleled the increase in ceramide, consistent with the generation of ceramide by the hydrolysis of sphingomyelin. The N-acetyl-conjugated sphingols (C2 ceramides) blocked phosphatidylethanol formation indicating that phospholipase D (PLD) is an intracellular target of ceramide action. These data suggest that ceramides, generated through activation of the sphingomyelin cycle, act as negative regulators of Fc(gamma)R-mediated phagocytosis.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor 48109, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Suchard
authors.forename: V
authors.initials: V
authors.lastname: Hinkovska-Galcheva
authors.forename: P J
authors.initials: PJ
authors.lastname: Mansfield
authors.forename: L A
authors.initials: LA
authors.lastname: Boxer
authors.forename: J A
authors.initials: JA
authors.lastname: Shayman
mesh_terms: D002518:Ceramides / Q000096:biosynthesis / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004912:Erythrocytes / Q000276:immunology; D020404:Glycerophospholipids; D006801:Humans; D007074:Immunoglobulin G / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects*; D010712:Phosphatidic Acids / Q000096:biosynthesis; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
chemical_list: D002518:Ceramides; D020404:Glycerophospholipids; D007074:Immunoglobulin G; C064769:N-acetylsphingosine; D010712:Phosphatidic Acids; C051521:phosphatidylethanol; D009240:N-Formylmethionine Leucyl-Phenylalanine; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine