Interaction of monocytic cells with respiratory syncytial virus results in activation of NF-kappaB and PKC-alpha/beta leading to up-regulation of IL-15 gene expression.
Respiratory syncytial virus (RSV) is a major human respiratory pathogen, particularly for infants. RSV is also a powerful inducer of cytokines, one of which is IL-15, an important immunoregulatory cytokine. IL-15 plays a key role in NK and T cell development and differentiation and also regulates NK cell/macrophage interaction, as well as monocyte/macrophage and granulocyte function. We have shown previously that different viruses up-regulate IL-15 gene expression in human PBMCs. Recently, we found that RSV induces the expression of IL-15 mRNA in the monocytic line THP-1. The signaling pathway involved in such virus-induced up-regulation of IL-15 has not yet been identified. We report here a study describing this mechanism. Because of the involvement of the protein kinase C (PKC) and the transcription factor NF-kappaB in the regulation of others cytokines by RSV as well as the involvement of NF-kappaB in the transactivation of IL-15, our hypothesis was that RSV induced the expression of IL-15 in THP-1 cells through the PKC and NF-kappaB activation. We demonstrate here that RSV-induced up-regulation of IL-15 expression in THP-1 cells involves the phosphorylation of PKC-alpha/beta. Further, inhibition of PKC by different specific inhibitors blocks this up-regulation. Using the electromobility shift assay, we show that the activated form of NF-kappaB binds to the IL-15 promoter sequence. We further confirm, using an ELISA assay, the involvement of p65 in the transcription of IL-15. This study, demonstrating the ability of RSV to induce IL-15 expression, might explain, at least in part, the exacerbated, inflammatory response triggered by RSV infection.
Ennaciri
Jamila
J
Laboratory of Immunovirology, Sainte-Justine Hospital Research Center, Montreal, QC, Canada.
Ahmad
Rasheed
R
Menezes
José
J
D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics* / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D004791:Enzyme Inhibitors; D019409:Interleukin-15; D016328:NF-kappa B; D012333:RNA, Messenger; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha