Histamine metabolism and transport are deranged in human keratinocytes in oral lichen planus.

BACKGROUND: Recent reports have indicated that nonimmune cells can produce low concentrations of histamine. This observation, together with the discovery of the high-affinity histamine H(4) receptor (H(4) R), has added additional layers of complexity to our understanding of histamine signalling. Human oral keratinocytes (HOKs) possess a uniform H(4) R pattern, which is deranged in oral lichen planus (OLP). OBJECTIVES: To investigate histamine metabolism and transport in HOKs of healthy controls and patients with OLP. METHODS: Tissue sections and cultured primary HOKs were studied using immunostaining, quantitative real-time polymerase chain reaction and confocal microscopy. Histamine levels were analysed using high-performance liquid chromatography. RESULTS: l-histidine decarboxylase (HDC) and organic cation transporter (OCT)3 were increased in mRNA and protein levels in patients with OLP compared with controls. In contrast, histamine N-methyltransferase (HNMT) immunoreactivity was decreased in OLP. OCT1/OCT2 and diamine oxidase were not detectable in either tissue sections or in HOKs. Immunolocalization of HDC and OCT3 in HOKs revealed moderate-to-high expression within cytoplasm and cell boundaries. Stimulation with lipopolysaccharide (LPS) or interferon-gamma upregulated HDC-gene transcript in HOKs, whereas this was downregulated with high histamine concentration and tumour necrosis factor-alpha. LPS induced a dose-dependent release of low histamine in HOKs, while high histamine concentration downregulated epithelial adhesion proteins. CONCLUSIONS: HOKs are histamine-producing cells. They release histamine via OCT3 channels in concentrations too low to activate the classical low-affinity H(1) R and H(2) R, but high enough to stimulate the high-affinity H(4) R in autocrine and paracrine modes. The substantially deranged histamine metabolism and transport in OLP could, in part, contribute to the disease pathogenesis.