[Show abstract][Hide abstract] ABSTRACT: As most solid tumors are hypoxic, dendritic cells (DC) in solid tumors are also exposed to hypoxia. While many adaptation responses of tumor cells to hypoxia are known, it is yet to be determined how hypoxia affects the functions of DC. To explore the effects of hypoxia on the functions of DC, we compared the expression of surface markers, cytokines, chemokine receptors and matrix metalloproteinases (MMP) of human monocyte-derived DC (hmDC) differentiated under hypoxia to those differentiated under normoxia. Both groups of hmDC expressed similar levels of surface markers and cytokines. However, expression of MMP-9 and membrane type-1-MMP, as well as migrating activity, was significantly suppressed in hmDC differentiated under hypoxia compared with their normoxia counterparts. We also demonstrated that trichostatin A restored the production of MMP-9 in hmDC, under hypoxia. Collectively, our findings show that a hypoxic microenvironment suppresses the production of MMP in hmDC, most probably through the deacetylation of promoter regions of MMP, thus suppressing the migrating activity of hmDC. Our results suggest that the hypoxic microenvironment in solid tumor tissues may suppress the function of DC.
European Journal of Immunology 12/2005; 35(12):3468-77. DOI:10.1002/eji.200526262 · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have recently demonstrated that granulocyte colony-stimulating factor (G-CSF) stimulated the production of epithelial-cell-derived-neutrophil attractant-78 (ENA-78) by neutrophils and that ENA-78 might promote the accumulation of neutrophils that had migrated from the intravascular space into inflammatory tissues. In this study, we examined whether other chemokines could be secreted by neutrophils that had accumulated after migrating from the intravascular space into the inflammatory tissues. We demonstrated that adhesion to laminin contained in the basement membrane and Matrigel, which is an artificial basement membrane model, induced macrophage inflammatory protein-1 beta (MIP-1 beta) in neutrophils and that MIP-1 beta secreted by neutrophils induced the chemotaxis of dendritic cells. These findings suggest that neutrophils transmigrating through the basement membrane are stimulated to secrete MIP-1 beta by the basement membrane, inducing the transmigration of dendritic cells from the intravascular space into inflammatory tissues. We propose that neutrophils intervene between innate immune response and specific immune response by secreting MIP-1 beta during the transmigration through the basement membrane.
British Journal of Haematology 01/2005; 127(5):592-7. DOI:10.1111/j.1365-2141.2004.05242.x · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the tumor cells exposed to hypoxia, hypoxia-inducible factor-1 (HIF-1)-mediated adaptation responses such as angiogenesis and anaerobic metabolism are induced for their survival. We have recently reported that the constitutive expression of HIF-1 alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and glucose deprivation. We then established dominant-negative HIF-1 alpha (dnHIF-1 alpha) transfectants and examined their susceptibility to apoptosis and growth inhibition induced by hypoxia and glucose deprivation in vitro and their tumorigenicity in SCID mice. We further examined the expressions of aldolase A and Glut-1 in vitro and Glut-1 expression and glucose uptake in the tumor tissues and microvessel counts in the tumor tissues. As a result, dnHIF-1 alpha rendered the pancreatic cancer cells sensitive to apoptosis and growth inhibition induced by hypoxia and glucose deprivation. Also it abrogated the enhanced expression of Glut-1 and aldolase A mRNAs under hypoxia and reduced the expression of Glut-1 and the glucose uptake in the tumor tissues and consequently in vivo tumorigenicity. We found no significant difference in the microvessel counts among the tumor tissues. From these results, we suggest that the disruption of the HIF-1 pathway might be effective in the treatment of pancreatic cancers.
American Journal Of Pathology 05/2003; 162(4):1283-91. DOI:10.1016/S0002-9440(10)63924-7 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since it is reported that adrenomedullin (AM) upregulated by hypoxia inhibits hypoxic cell death, we examined the effects of AM antagonist (AM C-terminal fragment; AM(22-52)) on the growth of pancreatic cancer cells. We, for the first time, demonstrated that AM antagonist significantly reduced the in vivo growth of the pancreatic cancer cell line. Immunohistochemical analysis demonstrated that the mean diameter of blood vessels was significantly smaller in the tumor tissues treated with AM antagonist than in those treated with AM N-terminal fragment (AM(1-25)), and that the PCNA-labeling index was lower in the former than in the latter. Then we demonstrated that AM antagonist showed no effect on the in vitro growth of the pancreatic cancer cell line. These results showed that AM played an important role in the growth of pancreatic cancer cells in vivo, suggesting that AM antagonist might be a useful tool for treating pancreatic cancers.
[Show abstract][Hide abstract] ABSTRACT: We have previously reported that transforming growth factor beta (TGF-beta) produced by rat hepatoma cell line KDH-8 cells suppressed the interleukin-2 (IL-2) production of T cells and the tumoricidal activity of macrophages in KDH-8 tumor-bearing rats and that the inhibition of TGF-beta production by low-dose bleomycin restored these activities significantly. In this study, we established three transfectant clones with stable expression of soluble TGF-beta receptor type II (sTRII), namely KT1, KT2 and KT3, and one with an empty vector used as control vector (KV), and then investigated the effects of sTRII on the tumorigenicity of KDH-8 cells and immune responses in syngeneic Wistar King Aptekman/Hok (WKAH) rats. We found that sTRII expressed in sTRII transfectants could abolish growth inhibition of Mv1Lu cells by TGF-beta1 produced by the cells themselves, and that tumor growth of KT2 and KT3 clones in vivo was suppressed significantly compared with that of parent, KV and KT1 clones. Furthermore, we demonstrated that IL-2 production of splenocytes and IL12p40 mRNA expression in tumor tissues were restored in rats inoculated with KT2 and KT3 clones, whereas such restoration was not observed in rats inoculated with parent, KV and KT1 clones. Combined with a low expression of sTRII in KT1 tumor tissues, these results suggest that sTRII may to some extent be able to abolish the tumor-promoting activity of TGF-beta, and imply that sTRII might have a therapeutic effect on TGF-beta-producing tumors.
Cancer Immunology and Immunotherapy 10/2002; 51(7):381-8. DOI:10.1007/s00262-002-0290-6 · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Taxol is an effective anti-tumour drug against a variety of tumour cells. Taxol directly induces apoptosis in addition to a G2/M cell cycle arrest. However, it remains poorly understood how Taxol induces apoptosis in tumour cells. Taxol induces the secretion of inflammatory cytokines in murine macrophages in a toll-like receptor-4 (TLR-4)-dependent manner in addition to its anti-tumour effects, but the effect of Taxol on human macrophages is controversial. In this study, we demonstrated that low doses (less than 1000 nmol/l) of Taxol induced the expression of tumour necrosis factor (TNF)-alpha in human myelomonocytic cells and that the induction of TNF-alpha mRNA was inhibited by dominant-negative myeloid differentiation protein (dnMyD88). Furthermore, we demonstrated that the same doses of Taxol induced apoptosis of the same myelomonocytic cells and that the Taxol-induced apoptosis was also inhibited by dnMyD88. In accordance with the previous reports, Taxol induced the expression of TNF-alpha and apoptosis in a TLR4-independent manner. These results suggest that TNF-alpha expression and apoptosis, both induced by Taxol in human myelomonocytic cells, share the signal transduction molecule MyD88.
British Journal of Haematology 09/2002; 118(2):638-45. DOI:10.1046/j.1365-2141.2002.03645.x · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Whereas mobilization to inflammatory sites is an important function of neutrophils, it remains to be determined whether granulocyte colony-stimulating factor (G-CSF) stimulates the mobilization of neutrophils to the inflammatory sites. This study compared the expression of more than 9000 genes in neutrophils treated with and without G-CSF with the use of a DNA microarray system to determine the effects of G-CSF on the function of neutrophils. It was found that messenger RNA expression of epithelial cell-derived neutrophil attractant-78 (ENA-78), which has been reported to be a chemotactic factor for neutrophils, was induced by G-CSF in neutrophils. The study demonstrated that the supernatant of G-CSF-treated neutrophils induced the chemotaxis of neutrophils and that anti-ENA-78 antibody and anti-CXCR-2 antibody inhibited the chemotaxis. These data suggest that G-CSF may enhance the mobilization of neutrophils and consequently augment the accumulation of neutrophils in the inflammatory sites through the secretion of ENA-78.
[Show abstract][Hide abstract] ABSTRACT: To elucidate the mechanisms by which haemopoietic progenitor cells lodge in the bone marrow, we examined the secretion of chemoattractants for haemopoietic progenitor cells by bone marrow and lung endothelial cells. The bone marrow endothelial cells, but not lung endothelial cells, secreted chemoattractants for the haemopoietic progenitor cell line, FDCP-2, and normal haemopoietic progenitor cells. Checkerboard analysis demonstrated that the conditioned medium of the bone marrow endothelial cells had chemotactic activity and random motility-stimulating activity. The bone marrow endothelial cells expressed stromal-cell-derived factor-1 (SDF-1) mRNA and produced SDF-1 protein, whereas the lung endothelial cells did not. Adhesion of FDCP-2 cells to the bone marrow endothelial cells was partially inhibited by anti-SDF-1 antibody. These findings suggest that the chemoattractants for haemopoietic progenitor cells including SDF-1 and random motility-stimulating factor(s) selectively secreted by the bone marrow endothelial cells may contribute to the homing of haemopoietic progenitor cells to bone marrow.
British Journal of Haematology 08/1999; 106(4):905 - 911. DOI:10.1046/j.1365-2141.1999.01644.x · 4.71 Impact Factor