title: Apoptotic cells can deliver chemotherapeutics to engulfing macrophages and suppress inflammatory cytokine production.
abstract: Immunosuppression via cell-cell contact with apoptotic cells is a well studied immunological phenomenon. Although the original studies of immune repression used primary cells, which undergo spontaneous cell death or apoptosis in response to irradiation, more recent studies have relied on chemotherapeutic agents to induce apoptosis in cell lines. In this work, we demonstrate that Jurkat cells induced to die with actinomycin D suppressed inflammatory cytokine production by macrophages, whereas cells treated with etoposide did not. This immune repression mediated by actinomycin D-treated cells did not require phagocytosis or cell-cell contact and thus occurs through a different mechanism from that seen with primary apoptotic neutrophils. Moreover, cells induced to die with etoposide and then treated for a short time with actinomycin D also suppressed macrophage responses, indicating that suppression was mediated by actinomycin D independent of the mechanism of cell death. Finally, phagocytosis of actinomycin D-treated cells caused apoptosis in macrophages, and suppression could be blocked by inhibition of caspase activity in the target macrophage. Together, these data indicate that apoptotic cells act as "Trojan horses," delivering actinomycin D to engulfing macrophages. Suppression of cytokine production by macrophages is therefore due to exposure to actinomycin D from apoptotic cells and is not the result of cell-receptor interactions. These data suggest that drug-induced death may not be an appropriate surrogate for the immunosuppressive activity of apoptotic cells. Furthermore, these effects of cytotoxic drugs on infiltrating immune phagocytes may have clinical ramifications for their use as antitumor therapies.
authors.affiliation: Program of Developmental Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Perez
authors.forename: Nicholas
authors.initials: N
authors.lastname: Paquette
authors.forename: Helena
authors.initials: H
authors.lastname: Païdassi
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.forename: Kristin
authors.initials: K
authors.lastname: White
authors.forename: Rachel
authors.initials: R
authors.lastname: Skvirsky
authors.forename: Adam
authors.initials: A
authors.lastname: Lacy-Hulbert
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Stuart
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D005047:Etoposide