We reported in recent publication that bacterial lipopolysaccharides (LPS) and mast cells are involved in the pathogenesis of the premalignant lesion, oral lichen planus (OLP). However, the mechanisms beyond such effect remain unknown. We therefore investigated the role of the antimicrobial peptide response, via human β-defensin 2 (hBD-2), in promoting OLP pathology and its potential contribution to oral squamous cell carcinoma (OSCC).
Biopsies from premalignant oral lichen planus (OLP) patients, OTSCC patients and healthy controls were used. Two OTSCC cell-lines and normal human keratinocytes (HOKs) were used for in vitro studies. HBD-2 and other targets were mapped by immunohistochemistry and double-labelling immunofluorescence. Immunoreactivity was analysed by ImageJ2 software. The highly sensitive droplet-digital PCR technology and qRT-PCR were utilized to study the clinical- and in vitro-derived samples, respectively. H4R was challenged with the specific agonist HST-10 and the inverse agonists/antagonists ST-1007.
hBD-2 was highly induced in OLP lesions. The expression was lower in OTSCC tissues while very low levels of hBD-2 mRNA were observed in OTSCC cells. Mast cells were the main non-epithelial producers of hBD-2 in OLP lesions. Histamine synergistically induced TNF-α- and IFN-γ-mediated production of hBD-2 in HOKs. Furthermore, H4R activation inhibited TNF-α-mediated induction of epithelial hBD-2 while ST-1007 reversed such effect.
Dysregulated production of hBD-2 could enhance a proinflammatory vicious circle in OLP, which can further damage healthy neighbouring cells and may over time promote carcinogenesis. Histamine and H4R can modulate hBD-2 response in oral epithelium and may serve as promising targets for therapeutic interventions.
TULES Research Group.
Doctoral Program in Oral Sciences, University of Helsinki.
All authors have declared no conflicts of interest.