IMMUNOBIOLOGY Requirement of TLR2-mediated signaling for the induction of IL-15 gene expression in human monocytic cells by HSV-1

Exposure of human monocytic cells to herpes simplex virus type 1 (HSV-1) results in immediate up-regulation of interleukin (IL)–15 gene expression. However, the receptor involved in this induction is not known. Here, we provide evidence that this induction depends on TLR2mediated signaling pathway. Through the use of small interfering RNAs (siRNAs), we demonstrate that HSV-1–induced upregulation of IL-15 gene expression in monocytic THP1 cells requires the presence of the adaptors MyD88, IRAK1, and TRAF6. Interestingly, TIRAP/Mal, an adaptor molecule specifically recruited to TLR2 and TLR4, was also required for maximal up-regulation of IL-15. This response was completely abrogated by anti-TLR2, but not anti-TLR4, blocking mAbs in both primary monocytes and THP1 cells. Furthermore, THP1 cells rendered defective in TLR2 expression by disrupting the expression of Sp1, a major transcription factor involved in TLR2 promoter activity, were unable to up-regulate IL-15 gene expression in response to HSV-1. In addition, HSV-1–induced NFB activation was significantly reduced after neutralization of TLR2 and the adaptor proteins. Altogether, these results unequivocally show that HSV-1 induces TLR2-dependent activation of IL-15 gene expression, which requires the recruitment of both MyD88 and TIRAP/Mal and the activation of IRAK1 and TRAF6 leading to NFB translocation to the nucleus. (Blood. 2008;112: 2360-2368)