title: Requirement of TLR2-mediated signaling for the induction of IL-15 gene expression in human monocytic cells by HSV-1.
abstract: 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 TLR2-mediated signaling pathway. Through the use of small interfering RNAs (siRNAs), we demonstrate that HSV-1-induced up-regulation 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 NF-kappaB 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 NF-kappaB translocation to the nucleus.
authors.affiliation: Laboratory of Immunovirology and Viral & Immune Diseases Program, Ste-Justine Hospital Research Center and Department of Microbiology & Immunology, Faculty of Medicine, University of Montreal, QC, Canada.
authors.forename: Rasheed
authors.initials: R
authors.lastname: Ahmad
authors.forename: Souad
authors.initials: S
authors.lastname: El Bassam
authors.forename: Paulo
authors.initials: P
authors.lastname: Cordeiro
authors.forename: José
authors.initials: J
authors.lastname: Menezes
mesh_terms: D005786:Gene Expression Regulation; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000821:virology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D019409:Interleukin-15; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases