Hypoxia suppresses the production of matrix metalloproteinases and the migration of human monocyte-derived dendritic cells.
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.
Zhao
Wenli
W
Department of Pathological Oncology, Division of Cancer Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Darmanin
Stephanie
S
Fu
Qiang
Q
Chen
Jian
J
Cui
Hongyan
H
Wang
Jingxin
J
Okada
Futoshi
F
Hamada
Jun-ichi
J
Hattori
Yuu-ichi
Y
Kondo
Takeshi
T
Hamuro
Junji
J
Asaka
Masahiro
M
Kobayashi
Masanobu
M
D015415:Biomarkers; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000201:enzymology*; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D009000:Monocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000502:physiology
D015415:Biomarkers; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1