期刊
JOURNAL OF IMMUNOLOGY
卷 200, 期 12, 页码 4180-4189出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1800241
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资金
- National Institutes of Health Grant [CA 165469]
- Flow Cytometry and Biospecimen Procurement and Translational Pathology shared resource facilities of the Markey Cancer Center [P30CA177558]
- Alzheimer's Disease Center Grant at the University of Kentucky [P30-AG028383]
Chronic lymphocytic leukemia (CLL) patients progressively develop an immunosuppressive state. CLL patients have more plasma IL-10, an anti-inflammatory cytokine, than healthy controls. In vitro human CLL cells produce IL-10 in response to BCR cross-linking. We used the transgenic E mu-T cell leukemia oncogene-1 (TCL1) mouse CLL model to study the role of IL-10 in CLL associated immunosuppression. E mu-TCL mice spontaneously develop CLL because of a B cell-specific expression of the oncogene, TCL1. E mu-TCL1 mouse CLL cells constitutively produce IL-10, which is further enhanced by BCR cross-linking, CLL-derived IL-10 did not directly affect survival of murine or human CLL cells in vitro. We tested the hypothesis that the CLL-derived IL-10 has a critical role in CLL disease in part by suppressing the host immune response to the CLL cells. In IL-10R(-/-) mice, wherein the host immune cells are unresponsive to IL-10-mediated suppressive effects, there was a significant reduction in CLL cell growth compared with wild type mice. IL-10 reduced the generation of effector CD4 and CD8 T cells. We also found that activation of BCR signaling regulated the production of IL-10 by both murine and human CLL cells. We identified the transcription factor, Sp1, as a novel regulator of IL-10 production by CLL cells and that it is regulated by BCR signaling via the Syk/MAPK pathway. Our results suggest that incorporation of IL-10 blocking agents may enhance current therapeutic regimens for CLL by potentiating host antitumor immune response.
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