RESUMO
The immune system can both promote and suppress cancer. Chronic inflammation and proinflammatory cytokines such as interleukin (IL)-1 and IL-6 are considered to be tumour promoting. In contrast, the exact nature of protective antitumour immunity remains obscure. Here, we quantify locally secreted cytokines during primary immune responses against myeloma and B-cell lymphoma in mice. Strikingly, successful cancer immunosurveillance mediated by tumour-specific CD4(+) T cells is consistently associated with elevated local levels of both proinflammatory (IL-1α, IL-1ß and IL-6) and T helper 1 (Th1)-associated cytokines (interferon-γ (IFN-γ), IL-2 and IL-12). Cancer eradication is achieved by a collaboration between tumour-specific Th1 cells and tumour-infiltrating, antigen-presenting macrophages. Th1 cells induce secretion of IL-1ß and IL-6 by macrophages. Th1-derived IFN-γ is shown to render macrophages directly cytotoxic to cancer cells, and to induce macrophages to secrete the angiostatic chemokines CXCL9/MIG and CXCL10/IP-10. Thus, inflammation, when driven by tumour-specific Th1 cells, may prevent rather than promote cancer.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Inflamação/imunologia , Linfoma de Células B/imunologia , Macrófagos/imunologia , Mieloma Múltiplo/imunologia , Neoplasias/imunologia , Proteínas Angiostáticas/biossíntese , Proteínas Angiostáticas/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular Tumoral , Quimiocina CXCL10/biossíntese , Quimiocina CXCL10/imunologia , Quimiocina CXCL9/biossíntese , Quimiocina CXCL9/imunologia , Imuno-Histoquímica , Inflamação/metabolismo , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-12/biossíntese , Interleucina-12/imunologia , Interleucina-1alfa/biossíntese , Interleucina-1alfa/imunologia , Interleucina-1beta/biossíntese , Interleucina-1beta/imunologia , Interleucina-2/biossíntese , Interleucina-2/imunologia , Interleucina-6/biossíntese , Interleucina-6/imunologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos SCID , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais , Células Th1/imunologia , Células Th2/imunologia , Microambiente TumoralRESUMO
HDAC inhibitors are promising anticancer agents that induce cell cycle arrest and apoptosis. However, the role of HDACs in cancer progression, such as angiogenesis and metastasis, remains largely unexplored. Among various HDAC inhibitors, we demonstrate that TSA and SAHA upregulated the expression of angiostatic ADAMTS1 in A549 cells. HDAC6 inhibitor tubacin, and knockdown of HDAC6, also lead to ADAMTS1 upregulation. By reporter, DAPA, and ChIP assays, the proximal GC boxes were demonstrated to be essential for ADAMTS1 induction. Decreased binding of SP1 and HDAC6 to the ADAMTS1 promoter after TSA treatment was also seen. These data suggest the involvement of HDAC6 and SP1 in the HDACi-induced expression of angiostatic ADAMTS1.
