c-Jun N-terminal kinase negatively regulates dsRNA and RSV induction of tumor necrosis factor- alpha transcription in human epithelial cells.
Secretion of inflammatory cytokines is the initial step of the immune response to viral infections. This innate immune response is mediated by the expression of a variety of cytokines, exemplified by tumor necrosis factor- alpha (TNF-alpha). The presence of dsRNA during viral infections is a key step in activation of several signaling pathways, including protein kinase R (PKR), toll-like receptor 3 (TLR3), mitogen-activated protein kinase (MAPK), activator protein-1 (AP-1), interferon regulatory factors (IRFs), and NF-kappaB pathways, which are all relevant in the expression of inflammatory cytokines. We previously reported that PKR and p38 MAPK were required for dsRNA and viral induction of inflammatory cytokines in epithelial cells. Here, we report that activation of c-Jun N-terminal kinase (JNK) during dsRNA treatment or respiratory syncytial viral (RSV) infection negatively regulates the induction of TNF-alpha in human epithelial cells. Inhibition of JNK by a pharmacologic inhibitor showed that expression of TNF-alpha increased following both dsRNA treatment and infection with RSV. Importantly, transfection of epithelial cells with a dominant-negative mutant of JNK significantly increased dsRNA induction of TNF-alpha. The mechanism by which JNK inhibition increases TNF-alpha induction appears to be through p38 MAPK activation. Our data show that JNK is a negative regulator of dsRNA and RSV induction of TNF-alpha expression and, thus, may act as a counterbalance to proinflammatory signals generated during viral infections.
Stewart
Michael J
MJ
Laboratory of Respiratory Biology, NIEHS/NIH, Research Triangle Park, NC 27709, USA.
Kulkarni
Sandhya B
SB
Meusel
Tiffany R
TR
Imani
Farhad
F
D000873:Anthracenes / Q000494:pharmacology; D002460:Cell Line; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology / Q000821:virology; D005786:Gene Expression Regulation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000201:enzymology / Q000276:immunology / Q000821:virology*; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000873:Anthracenes; D047428:Protein Kinase Inhibitors; D012330:RNA, Double-Stranded; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases