title: Inhibition of p38MAPK and CD137 signaling reduce dengue virus-induced TNF-α secretion and apoptosis.
abstract: BACKGROUND
  Hepatic injury in dengue virus (DENV) infection is authenticated by hepatomegaly and an upsurge in transaminase levels. DENV replicates in hepatocytes and causes hepatocyte apoptosis both in vitro and in vivo. Understanding the molecular mechanisms of DENV-induced hepatic injury could facilitate the development of alternate chemotherapeutic agents and improved therapies.
  
  
  RESULTS
  The p38 mitogen-activated protein kinase (MAPK) participates in both apoptosis-related signaling and pro- inflammatory cytokine production. The role of p38 MAPK in DENV-infected HepG2 cells was examined using RNA interference. The results showed that DENV infection activated p38 MAPK and induced apoptosis. The p38 MAPK activation and TNF-α production were controlled by p38 MAPK and CD137 signaling in DENV-infected HepG2 cells as activated p38 MAPK, TNF-α and apoptosis were significantly decreased in p38 MAPK and CD137 depleted DENV-infected HepG2 cells. Addition of exogenous TNF-α to p38 MAPK depleted DENV-infected HepG2 cells restored DENV-induced apoptosis in HepG2 cells.
  
  
  CONCLUSIONS
  DENV induces CD137 signaling to enhance apoptosis by increasing TNF-α production via activation of p38 MAPK.
authors.affiliation: Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Amar
authors.initials: A
authors.lastname: Nagila
authors.forename: Janjuree
authors.initials: J
authors.lastname: Netsawang
authors.forename: Aroonroong
authors.initials: A
authors.lastname: Suttitheptumrong
authors.forename: Atthapan
authors.initials: A
authors.lastname: Morchang
authors.forename: Sasiprapa
authors.initials: S
authors.lastname: Khunchai
authors.forename: Chatchawan
authors.initials: C
authors.lastname: Srisawat
authors.forename: Chunya
authors.initials: C
authors.lastname: Puttikhunt
authors.forename: Sansanee
authors.initials: S
authors.lastname: Noisakran
authors.forename: Pa-thai
authors.initials: PT
authors.lastname: Yenchitsomanus
authors.forename: Thawornchai
authors.initials: T
authors.lastname: Limjindaporn
mesh_terms: D017209:Apoptosis; D003716:Dengue Virus / Q000276:immunology* / Q000472:pathogenicity*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000276:immunology / Q000502:physiology / Q000821:virology; D006801:Humans; D015398:Signal Transduction; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases
references.citation: Virus Res. 2010 Feb;147(2):275-83
references.pmid: 19944121
references.citation: J Virol. 2007 Jun;81(11):5518-26
references.pmid: 17360740
references.citation: Cell Signal. 2007 Sep;19(9):1899-908
references.pmid: 17855813
references.citation: J Virol. 1997 Apr;71(4):3244-9
references.pmid: 9060688
references.citation: J Virol. 2008 Dec;82(24):12312-24
references.pmid: 18842737
references.citation: Cell Signal. 2000 Jan;12(1):1-13
references.pmid: 10676842
references.citation: Biochem Biophys Res Commun. 2011 Jul 8;410(3):428-33
references.pmid: 21669186
references.citation: J Gen Virol. 2003 Oct;84(Pt 10):2781-2793
references.pmid: 13679613
references.citation: Biochem Biophys Res Commun. 2007 Oct 19;362(2):334-9
references.pmid: 17707345
references.citation: J Clin Virol. 2007 Sep;40(1):50-4
references.pmid: 17693133
references.citation: Arch Virol. 2009;154(8):1211-21
references.pmid: 19565324
references.citation: Virus Res. 2011 Mar;156(1-2):25-34
references.pmid: 21195733
references.citation: J Med Virol. 2010 Aug;82(8):1392-9
references.pmid: 20572077
references.citation: Virology. 2008 Nov 10;381(1):55-66
references.pmid: 18799179
references.citation: J Med Virol. 2009 Jun;81(6):1069-81
references.pmid: 19382257
references.citation: J Gen Virol. 2005 Apr;86(Pt 4):1055-1065
references.pmid: 15784899
references.citation: J Med Virol. 2004 Mar;72(3):436-44
references.pmid: 14748067
references.citation: Virology. 2010 Jan 5;396(1):30-6
references.pmid: 19897220
references.citation: J Gen Virol. 2011 Apr;92(Pt 4):807-18
references.pmid: 21148274
references.citation: Biochim Biophys Acta. 2007 Oct;1772(10):1158-66
references.pmid: 17964123
references.citation: Rev Infect Dis. 1989 May-Jun;11 Suppl 4:S826-9
references.pmid: 2665014
references.citation: Microbiol Immunol. 2009 Aug;53(8):442-50
references.pmid: 19659928
references.citation: Science. 1995 Nov 24;270(5240):1326-31
references.pmid: 7481820
references.citation: Microbes Infect. 2008 Aug-Sep;10(10-11):1124-32
references.pmid: 18606243
references.citation: J Gen Virol. 2003 Aug;84(Pt 8):2191-2195
references.pmid: 12867651