title: SB203580 Modulates p38 MAPK Signaling and Dengue Virus-Induced Liver Injury by Reducing MAPKAPK2, HSP27, and ATF2 Phosphorylation.
abstract: Dengue virus (DENV) infection causes organ injuries, and the liver is one of the most important sites of DENV infection, where viral replication generates a high viral load. The molecular mechanism of DENV-induced liver injury is still under investigation. The mitogen activated protein kinases (MAPKs), including p38 MAPK, have roles in the hepatic cell apoptosis induced by DENV. However, the in vivo role of p38 MAPK in DENV-induced liver injury is not fully understood. In this study, we investigated the role of SB203580, a p38 MAPK inhibitor, in a mouse model of DENV infection. Both the hematological parameters, leucopenia and thrombocytopenia, were improved by SB203580 treatment and liver transaminases and histopathology were also improved. We used a real-time PCR microarray to profile the expression of apoptosis-related genes. Tumor necrosis factor α, caspase 9, caspase 8, and caspase 3 proteins were significantly lower in the SB203580-treated DENV-infected mice than that in the infected control mice. Increased expressions of cytokines including TNF-α, IL-6 and IL-10, and chemokines including RANTES and IP-10 in DENV infection were reduced by SB203580 treatment. DENV infection induced the phosphorylation of p38MAPK, and its downstream signals including MAPKAPK2, HSP27 and ATF-2. SB203580 treatment did not decrease the phosphorylation of p38 MAPK, but it significantly reduced the phosphorylation of MAPKAPK2, HSP27, and ATF2. Therefore, SB203580 modulates the downstream signals to p38 MAPK and reduces DENV-induced liver injury.
authors.affiliation: Department of Anatomy, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Gopinathan Pillai
authors.initials: GP
authors.lastname: Sreekanth
authors.affiliation: Department of Anatomy, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Aporn
authors.initials: A
authors.lastname: Chuncharunee
authors.affiliation: Department of Anatomy, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Aunchalee
authors.initials: A
authors.lastname: Sirimontaporn
authors.affiliation: Department of Anatomy, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Jutatip
authors.initials: J
authors.lastname: Panaampon
authors.affiliation: Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Bangkok, Thailand.
authors.forename: Sansanee
authors.initials: S
authors.lastname: Noisakran
authors.affiliation: Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Pa-Thai
authors.initials: PT
authors.lastname: Yenchitsomanus
authors.affiliation: Department of Anatomy, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Thawornchai
authors.initials: T
authors.lastname: Limjindaporn
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D000818:Animals; D003716:Dengue Virus / Q000472:pathogenicity*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D007093:Imidazoles / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000821:virology; D008107:Liver Diseases / Q000188:drug therapy* / Q000821:virology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000627:therapeutic use*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D051698:Activating Transcription Factor 2; D055551:HSP27 Heat-Shock Proteins; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C093642:SB 203580