Enhanced Apoptotic Cell Clearance Capacity and B Cell Survival Factor Production by IL-10-Activated Macrophages: Implications for Burkitt’s Lymphoma

Abstract

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.

Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1

“…It has been shown that macrophages, regulated by IL-10, have the potential to promote BL pathogenesis, firstly, through suppression of antitumor immunity following enhanced engulfment of apoptotic tumor cells and, secondly, through increased production of tumor cell growth/ survival factors. 75 In summary, this study reveals a novel physiological role of PARP-1 in the regulation of IL-10 induced uniquely by apoptotic cell-derived signals, and provides a clear molecular mechanism whereby individual IL-10 promoter haplotypes confer differential IL-10 production. Further investigation and elucidation of the molecular nature and characteristics of PARP-1-mediated immunoregulation will likely benefit the design of effective therapeutic strategies against a wide range of inflammatory and pathological conditions such as SLE, arthritis, asthma, sepsis, cardiomyopathy, stroke, inflammatory bowel disease, diabetes and cancer.…”

Immunobiology of the TAM receptors

“…An interaction between TAM and cytokine receptors during homeostatic phagocytosis has not been clearly demonstrated. However, IL-10 has been found to stimulate the phagocytosis of apoptotic cells by monocytes and macrophages 53,54 , and GAS6 and MER are among the monocyte genes that are upregulated by IL-10 (REF. 55 ).…”

Interleukin-6 and Interleukin-10 Gene Promoter Polymorphisms and Risk of Endemic Burkitt Lymphoma

“…17 Like IL-6, high levels of IL-10 in eBL tumor microenvironment also seem to be important in tumorigenesis and growth through multiple mechanisms. 15 It has been shown to be an autocrine growth factor for Burkitt-derived cell lines, 18,19 and it is frequently expressed in various B-cell malignancies. 14,20 IL-10 has been well-characterized as a protumorigenic cytokine with immunosuppressive effects by way of inhibition of interferon-γ, proinflammatory T-helper-1 lymphocytes, and cytotoxic T cells, 21 which are central mediators in control of EBV; hence, they potentially contribute to EBV and tumor escape from immune surveillance and enhance tumor growth.…”

“…14 Both IL-6 and IL-10 have been shown to be highly expressed in the BL tumor microenvironment, suggesting that they may be important signals in tumorigenesis. 15,16 IL-6 acts as a growth factor for EBV-infected B cells, resulting in increased Ig production and B-cell immortalization. 16 It has also been shown to be highly expressed in EBVimmortalized B cells, thereby promoting tumor growth.…”