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Hirozumi Sawai, Hitoshi Funahashi, Yuji Okada, Yoichi Matsuo, Yoichi Matsuo, Masaki Sakamoto, Minoru Yamamoto, Hiromitsu Takeyama, Tadao Manabe
Med Sci Monit 2005; 11(10): BR343-350
Background:Interleukin (IL)-1α plays an important role in modulating the expression of various growth factors and angiogenic factors in tumor cells. In here, we investigated effect of IL-1α on IL-8 secretion in human pancreatic cancer cells and underlying signal transduction pathways.Material/Methods:IL-8 expression and secretion by pancreatic cancer cells was measured by Western blot and enzyme-linked immunosorbent assay (ELISA), respectively. Activation of extracellular signal regulated kinases-1/2 (ERK-1/2), p38 mitogen-activated protein kinase (MAPK), c-jun aminoterminal kinase, Akt, and nuclear factor-κB (NF-κB) was determined by Western blot. Involvement of reactive oxygen species (ROS) were examined by measuring the H[sub]2[/sub]O[sub]2[/sub]. Activity of activator factor-1 (AP-1) and NF-κB was examined by electrophoretic mobility sift assay (EMSA). Proliferation of human umbilical vein endothelial cells (HUVECs) was determined by the 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide dye reduction method and cell count.Results:IL-1α modulated IL-8 secretion and induced activation of ERK-1/2 and p38 MAPK. Specific inhibitors for MEK-1 and p38 MAPK suppressed IL-8 secretion. IL-1α also induced production of ROS. Exogenous H[sub]2[/sub]O[sub]2[/sub] enhanced IL-8 secretion and N-acetyl cysteine (NAC) prevented IL-1α-induced ROS production and IL-8 secretion. EMSA confirmed that IL-1α increased DNA-binding activity of AP-1 and NF-κB. Inhibitors and ROS scavenger studies revealed that upstream signalings for AP-1 and NF-κB were MAPK and ROS, respectively. Conditioned media from pancreatic cancer cells pretreated with IL-1α remarkably stimulated in vitro HUVECs growth.Conclusions:These results suggest that MAPK/AP-1 and ROS/NF-κB signaling pathways are involved in IL-1α -induced IL-8 secretion and that these paracrine signaling pathways enhance endothelial cell proliferation.