Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt's lymphoma.
Burkitt's lymphoma (BL) is typified by frequent tumor cell apoptosis and significant macrophage infiltration. Since BL cells have an inherent tendency to undergo apoptosis at a high rate, we reasoned that macrophages in BL are functionally enhanced in at least two activities that have implications for tumor pathogenesis: 1) engulfment of apoptotic cells, an anti-inflammatory process known to suppress immune responses, and 2) production of BL cell survival factors that limit the extent of tumor cell apoptosis. In this study, we show that the microenvironment of BL is rich in the pleiotropic cytokine IL-10, which can be produced by both tumor cells and macrophages, and that IL-10-activated human macrophages have enhanced capacity to engulf apoptotic cells in vitro. This was found to be dependent on the macrophage tethering receptor of apoptotic cells, CD14. Furthermore, IL-10-activated macrophages were found to produce markedly higher levels of the B cell survival factor, B cell-activating factor of the TNF family/B lymphocyte stimulator (BAFF/BLyS) than macrophages matured in the absence of IL-10. Coculture of macrophages with BL cells further enhanced BAFF secretion. Significantly, we show that enhancement of BL cell survival by IL-10-activated macrophages is mediated by a BAFF-dependent component and that BAFF is produced at high levels by tumor-associated macrophages in situ. These results indicate that macrophages, regulated by IL-10, have the potential to promote BL pathogenesis, first, through suppression of antitumor immunity following enhanced engulfment of apoptotic tumor cells and, second, through increased production of tumor cell growth/survival factors.
Ogden
Carol Anne
CA
Centre for Inflammation Research, University of Edinburgh College of Medicine and Veterinary Medicine, Edinburgh, United Kingdom.
Pound
John D
JD
Batth
Balvinder K
BK
Owens
Sarah
S
Johannessen
Ingolfur
I
Wood
Katrina
K
Gregory
Christopher D
CD
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002051:Burkitt Lymphoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010587:Phagocytosis / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000502:physiology
D000276:Adjuvants, Immunologic; D053264:B-Cell Activating Factor; D018950:Lipopolysaccharide Receptors; D008565:Membrane Proteins; C505719:TNFSF13B protein, human; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10