Cyclooxygenase-2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents.
Cyclooxygenase-2 (COX-2) is one of the important mediators of inflammation in response to viral infection, and it contributes to viral replication, for example, cytomegalovirus or hepatitis C virus replication. The role of COX-2 in dengue virus (DENV) replication remains unclear. In the present study, we observed an increased level of COX-2 in patients with dengue fever compared with healthy donors. Consistent with the clinical data, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. Using cell-based experiments, we revealed that DENV-2 infection significantly induced COX-2 expression and prostaglandin E2(PGE2) production in human hepatoma Huh-7 cells. The exogenous expression of COX-2 or PGE2treatment dose-dependently enhanced DENV-2 replication. In contrast, COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. In an ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection. By using COX-2 promoter-based analysis and specific inhibitors against signaling molecules, we identified that NF-κB and MAPK/JNK are critical factors for DENV-2-induced COX-2 expression and viral replication. Altogether, our results reveal that COX-2 is an important factor for DENV replication and can serve as a potential target for developing therapeutic agents against DENV infection.
Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.|Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei, Taiwan.
Chun-Kuang
CK
Lin
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Chin-Kai
CK
Tseng
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yu-Hsuan
YH
Wu
Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.|Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
Chih-Chuang
CC
Liaw
School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Chun-Yu
CY
Lin
School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Chung-Hao
CH
Huang
School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center for Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan.
Yen-Hsu
YH
Chen
Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.|Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan.
Jin-Ching
JC
Lee
D000818:Animals; D000833:Animals, Suckling; D000998:Antiviral Agents / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D003715:Dengue / Q000188:drug therapy / Q000201:enzymology / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects / Q000502:physiology*; D015232:Dinoprostone / Q000096:biosynthesis; D006801:Humans; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
D000998:Antiviral Agents; D022762:CCAAT-Enhancer-Binding Proteins; D016328:NF-kappa B; D009578:Nitrobenzenes; D034741:RNA, Small Interfering; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone