Increased migration of Langerhans cells in response to HPV16 E6 and E7 oncogene silencing: role of CCL20

Abstract

Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The persistence or progression of cervical lesions suggests that viral antigens are not adequately presented to the immune system. This hypothesis is reinforced by the observation that most squamous intraepithelial lesions (SILs) show quantitative and functional alterations of Langerhans cells (LC). The infiltration of immature LC in the squamous epithelium is mainly controlled by Macrophage Inflammatory Protein 3alpha/CCL20. After having shown that CCL20 production is altered in HPV-transformed keratinocytes (KC), the possible role of HPV16 E6 and E7 viral oncoproteins in the reduced CCL20 levels observed in SILs was investigated by silencing HPV16 E6 and E7 oncogenes by RNA interference (siRNA). This treatment not only increased CCL20 secretion but also resulted in the modulation of NF-kappaB p50, p52 and p65 precursor localization. Moreover, silencing of E6 and E7 oncogenes in HPV16-transformed KC induced a significantly higher migratory capacity of LC in a Boyden chamber assay and in an in vitro formed (pre)neoplastic epithelium reminiscent of high-grade SILs. Anti-CCL20 neutralizing antibody experiments showed that the increased migration of LC is due to the re-expression of CCL20 in E6 and E7 siRNA transfected KC. These data suggest that HPV16 E6/E7-induced down-regulation of CCL20 observed during the cervical carcinogenesis may contribute to a diminished capacity of the immune system to control HPV infection.

Interferon-Induced Protection against Foot-and-Mouth Disease Virus Infection Correlates with Enhanced Tissue-Specific Innate Immune Cell Infiltration and Interferon-Stimulated Gene Expression

“…These chemokines are involved in the recruitment and proliferation of DCs and NK cells and have been shown to be coordinately induced after murine cytomegalovirus infection (48). In particular, MIP-3␣ has been described to control the migration of skin DCs (9). Therefore, the upregulation of these chemokines may be involved in the observed increase of DCs in IFN-treated animals which may have a role in the protection of the animals against FMDV.…”

Association of polymorphism in FcGR3A gene and progression of low-grade precursor lesions of cervical carcinoma

“…Recent observations sug- gest that the uptake of these complexes via Fc␥R leads to maturation on DCs and cross-presentation of antigens, resulting in tumor immunity [21,22]. It has been demonstrated that SILs show quantitative and functional alterations in DCs [23][24][25]. We decided to study the association of FcGR3A V158F polymorphism in two cohorts of women, one with regressed or stable LSIL and the other with HSIL with the hypothesis that this polymorphism may promote different capabilities in DCs or other immune cells for recognition of antibody-antigen complexes, development of ADCC and apoptosis.…”

Human Papillomavirus Biology, Pathogenesis, and Potential for Drug Discovery: A Literature Review for HIV Nurse Clinical Scientists

“…Articles focusing on the following were excluded: condylomata acuminate, abnormal cytology, vaccine titers, genotyping, HPV biology only in females, HPV head and neck cancers, basic viral infection, proctology, and herpes simplex virus. Table 1 Burk et al, 2009;Da Costa et al, 2002;Day & Schelhaas, 2014;Doorbar et al, 2006;Duncan et al, 2015;Guiguet et al, 2009;Hessol et al, 2009;Joyce et al, 1999;Kajitani et al, 2012;Machalek et al, 2012;Matthews et al, 2003;Middleton et al, 2003;Morshed et al, 2014;Munger et al, 2004;Pokomandy et al, 2011;Pyeon et al, 2009;Roden et al, 2001;Schiller et al, 2010;Stanley et al, 2012;Strickler et al, 2005;Uronis & Bendell, 2007 Use of HTS for drug discovery Basu et al, 2011;Buck et al, 2006;Huang et al, 2012;Kumar et al, 2011;Mahida et al, 2013;Marin et al, 2015;Thompson et al, 2010 Note. HPV = human papilloma virus; HTS = high-throughput screening techniques.…”

“…E6 and E7 are the primary oncogenes in HPV and together they are responsible for dysplastic changes at the cellular level and the progression to invasive cancer. E6 and E7 function by inactivating p53 and retinoblastoma protein (pRb; Matthews et al, 2003). The normal functions of p53 and pRb are to enable cells to maintain cell cycle DNA potential (Munger et al, 2004).…”