TY - JOUR
T1 - Endosulfan induces COX-2 expression via NADPH oxidase and the ROS, MAPK, and Akt pathways
AU - Kim, Hyung Gyun
AU - Kim, Young Ran
AU - Park, Jin Hee
AU - Khanal, Tilak
AU - Choi, Jae Ho
AU - Do, Minh Truong
AU - Jin, Sun Woo
AU - Han, Eun Hee
AU - Chung, Young Ho
AU - Jeong, Hye Gwang
N1 - Funding Information:
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (NRF-2013R1A2A2A01067892), the Priority Research Centers Program through the National Research Foundation of Korea funded by Ministry of Education, Science and Technology (2009-0093815), and the Korea Basic Science Institute (D34400 to Y.H.C.), Republic of Korea.
Publisher Copyright:
© 2014, Springer-Verlag Berlin Heidelberg.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - Endosulfan (1,4,5,6,7,7-hexachloro-8,9,10-trinorborn-5-en-2,3-ylenebismet-hylene) is correlated with endocrine disruption, reproductive, and immune dysfunctions. Recently, endosulfan was shown to have an effect on inflammatory pathways, but its influence on cyclooxygenase-2(COX-2) expression is unclear. This study investigated the effects of COX-2 and molecular mechanisms by endosulfan in murine macrophage RAW 264.7 cells. Endosulfan significantly induced COX-2 protein and mRNA levels, as well as COX-2 promoter-driven luciferase activity and the production of prostaglandin E2, a major COX-2 metabolite. Transfection experiments with several human COX-2 promoter constructs revealed that endosulfan activated NF-κB, C/EBP, AP-1, and CREB. Moreover, Akt and mitogen-activated protein kinases (MAPK) were significantly activated by endosulfan. Moreover, endosulfan increased production of the ROS and the ROS-producing NAPDH-oxidase (NOX) family oxidases, NOX2, and NOX3. Endosulfan-induced Akt/MAPK pathways and COX-2 expression were attenuated by DPI, a specific NOX inhibitor, and the ROS scavenger N-acetylcysteine. These results demonstrate that endosulfan induces COX-2 expression via NADPH oxidase, ROS, and Akt/MAPK pathways. These findings provide further insight into the signal transduction pathways involved in the inflammatory effects of endosulfan.
AB - Endosulfan (1,4,5,6,7,7-hexachloro-8,9,10-trinorborn-5-en-2,3-ylenebismet-hylene) is correlated with endocrine disruption, reproductive, and immune dysfunctions. Recently, endosulfan was shown to have an effect on inflammatory pathways, but its influence on cyclooxygenase-2(COX-2) expression is unclear. This study investigated the effects of COX-2 and molecular mechanisms by endosulfan in murine macrophage RAW 264.7 cells. Endosulfan significantly induced COX-2 protein and mRNA levels, as well as COX-2 promoter-driven luciferase activity and the production of prostaglandin E2, a major COX-2 metabolite. Transfection experiments with several human COX-2 promoter constructs revealed that endosulfan activated NF-κB, C/EBP, AP-1, and CREB. Moreover, Akt and mitogen-activated protein kinases (MAPK) were significantly activated by endosulfan. Moreover, endosulfan increased production of the ROS and the ROS-producing NAPDH-oxidase (NOX) family oxidases, NOX2, and NOX3. Endosulfan-induced Akt/MAPK pathways and COX-2 expression were attenuated by DPI, a specific NOX inhibitor, and the ROS scavenger N-acetylcysteine. These results demonstrate that endosulfan induces COX-2 expression via NADPH oxidase, ROS, and Akt/MAPK pathways. These findings provide further insight into the signal transduction pathways involved in the inflammatory effects of endosulfan.
KW - COX-2
KW - Endosulfan
KW - NADPH oxidase
KW - ROS
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U2 - 10.1007/s00204-014-1359-7
DO - 10.1007/s00204-014-1359-7
M3 - Article
C2 - 25199686
AN - SCOPUS:84947572294
SN - 0340-5761
VL - 89
SP - 2039
EP - 2050
JO - Archives of Toxicology
JF - Archives of Toxicology
IS - 11
ER -