Herpes simplex virus-1 up-regulates IL-15 gene expression in monocytic cells through the activation of protein tyrosine kinase and PKC zeta/lambda signaling pathways.
IL-15 plays a seminal role in innate immunity through enhancing the cytotoxic function as well as cytokine production by NK and T cells. We have previously shown that exposure of PBMC as well as monocytic cells to different viruses results in immediate up-regulation of IL-15 gene expression and subsequent NK cell activation as an innate immune response of those cells to these viruses. However, no signaling pathway involved in this up-regulation has been identified. Here we show for the first time that HSV-1-induced up-regulation of IL-15 gene expression is independent of viral infectivity/replication. IL-15 gene is up-regulated by HSV-1 in human monocytes, but not in CD3+ T cells. HSV-1 induces the phosphorylation of protein tyrosine kinases (PTKs) and protein kinase C (PKC) for inducing IL-15 expression in monocytic cells. Inhibitors for PTKs reduced HSV-1-induced PTK activity, DNA binding activity of NF-kB as well as IL-15 gene expression. In contrast, an inhibitor for membrane-bound tyrosine kinases had no effect on these events. Experiments using PKC inhibitors revealed that phosphorylation of PKC zeta/lambda (PKC zeta/lambda), DNA binding activity of NF-kB and HSV-1-induced up-regulation of IL-15 were all decreased. Furthermore, we found that HSV-1-induced IL-15 up-regulation was also dependent on PTKs regulation of PKC phosphorylation. Thus, we conclude that IL-15 up-regulation in HSV-1-treated monocytic cells is dependent on the activity of both PTKs and PKC zeta/lambda.
Ahmad
Rasheed
R
Laboratory of Immunovirology and Viral and Immune Diseases Program, Sainte Justine Hospital Research Center, 3175 Chemin Cote Ste-Catherine, Montreal, QC, H3T 1C5, Canada.
Ennaciri
Jamila
J
Cordeiro
Paulo
P
El Bassam
Souad
S
Menezes
José
J
D004789:Enzyme Activation; D015870:Gene Expression; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D009000:Monocytes / Q000201:enzymology / Q000821:virology*; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
D019409:Interleukin-15; D007527:Isoenzymes; D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta