Defensins induce the recruitment of dendritic cells in cervical human papillomavirus-associated (pre)neoplastic lesions formed in vitro and transplanted in vivo.
In addition to their direct antimicrobial activity, defensins might also influence adaptive immunity by attracting immature dendritic cells (DC). As these cells have been shown to be deficient in uterine cervix carcinogenesis, we evaluated the ability of alpha-defensin (HNP-2, human neutrophil defensin 2) and beta-defensin (HbetaD2, human beta defensin 2) to stimulate their migration in human papillomavirus (HPV)-associated (pre)cancers. We first observed, using RT-PCR and immunohistology, that HbetaD2 is absent in HPV-transformed keratinocytes and that it is weakly expressed in cervical (pre)neoplastic lesions in comparison with normal keratinocytes. We next demonstrated that defensins exert a chemotactic activity for DC in a Boyden Chamber assay and stimulate their infiltration in an in vitro-formed (pre)neoplastic epithelium (organotypic culture of HPV-transformed keratinocytes). To evaluate the ability of defensins also to recruit DC in vivo, we developed a model of immunodeficient mice grafted with organotypic cultures of HPV+ keratinocytes, which form an epithelium similar to a high-grade neoplastic lesion, with tumoral invasion and neovascularization. Intravenously injected human DC were able to infiltrate grafts of HPV+ keratinocytes after administration of HNP-2 in the transplantation chamber. Taken together, these results suggest that defensins could reverse a frequent immune alteration observed in cancer development.
Hubert
Pascale
P
Department of Pathology B35, University Hospital of Liège, CHU Sart Tilman, 4000 Liège, Belgium. P.hubert@ulg.ac.be
Herman
Ludivine
L
Maillard
Catherine
C
Caberg
Jean-Hubert
JH
Nikkels
Arjen
A
Pierard
Gerald
G
Foidart
Jean-Marie
JM
Noel
Agnès
A
Boniver
Jacques
J
Delvenne
Philippe
P
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002461:Cell Line, Transformed; D002465:Cell Movement; D002584:Cervix Uteri / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D004848:Epithelium / Q000378:metabolism / Q000821:virology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology; D009924:Organ Culture Techniques; D027383:Papillomaviridae / Q000502:physiology; D030361:Papillomavirus Infections / Q000150:complications* / Q000378:metabolism; D011230:Precancerous Conditions / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D023084:alpha-Defensins / Q000276:immunology / Q000494:pharmacology*; D023083:beta-Defensins / Q000276:immunology / Q000494:pharmacology*; D002578:Uterine Cervical Dysplasia / Q000378:metabolism / Q000473:pathology / Q000821:virology
D023084:alpha-Defensins; D023083:beta-Defensins; C406416:human neutrophil peptide 2