Human adenovirus type 19 infection of corneal cells induces p38 MAPK-dependent interleukin-8 expression.
BACKGROUND
Human adenovirus type 19 (HAdV-19) is a major cause of epidemic keratoconjunctivitis, the only ocular adenoviral infection associated with prolonged corneal inflammation. In this study, we investigated the role of p38 mitogen-activated protein kinase (MAPK) in HAdV-19 infection, with particular attention to the role of p38 MAPK in the transcriptional control of interleukin-8 (IL-8), a chemokine previously shown to be central to the initiation of adenovirus keratitis.


RESULTS
We found that infection of corneal cells with HAdV-19 led to activation of p38 MAPK and its downstream targets, HSP-27 and ATF-2, within 15 to 30 minutes post-infection. Infection also induced phosphorylation of IkappaB and NFkappaB in a p38 MAPK-dependent fashion. Furthermore, HAdV-19 induced an interaction between p38 MAPK and NFkappaB-p65, followed by nuclear translocation of activated NFkappaB-p65 and its binding to the IL-8 promoter. The interaction between p38 MAPK and NFkappaB-p65 was inhibited in concentration-dependent fashion by SB203580, a chemical inhibitor of p38 MAPK, but not by SP600125, an inhibitor of JNK - another MAPK implicated in chemokine expression by HAdV-19 infected cells. IL-8 gene expression in HAdV-19 infection was significantly reduced in the presence of sequence-specific p38 MAPK siRNA but not control siRNA.


CONCLUSIONS
These results provide the first direct evidence for transcriptional regulation of IL-8 in HAdV-19 infected cells through the activation of the p38 MAPK signaling pathway. The p38 MAPK pathway may play a biologically important role in regulation of IL-8 gene expression in the adenovirus-infected cornea.
Rajaiya
Jaya
J
Molecular Pathogenesis of Eye Infection Research Center, Dean A, McGee Eye Institute, Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. jayabarathy-rajaiya@ouhsc.edu
Xiao
Jingnan
J
Rajala
Raju Vs
RV
Chodosh
James
J
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000258:Adenovirus Infections, Human / Q000378:metabolism*; D000260:Adenoviruses, Human; D002478:Cells, Cultured; D003315:Cornea; D015870:Gene Expression; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050863:Synaptotagmin I / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051698:Activating Transcription Factor 2; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D020672:I-kappa B Proteins; D016209:Interleukin-8; D018832:Molecular Chaperones; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D050863:Synaptotagmin I; D048051:p38 Mitogen-Activated Protein Kinases