IL-17C and its receptor IL-17RA/IL-17RE identify human oral epithelial cell as an inflammatory cell in recurrent aphthous ulcer.

BACKGROUND: Recurrent aphthous ulcer (RAU) is an ulcerative disease of non-keratinized oral mucosa. Colon and bronchial epithelial cells produce interleukin-17C (IL-17C) upon stimulation of Toll-like receptor 2 (TLR2), TLR3 and TLR5, which are highly expressed in epithelial cells in RAU lesions. We therefore investigated the eventual presence and function of IL-17C in cultured human oral keratinocytes (HOK) and control biopsies compared to RAU lesions. METHODS: Expression of IL-17A, IL-17C, IL-17RA and IL-17RE was analysed in cultured HOK cells using quantitative real-time polymerase chain reaction (qRT-PCR). HOK cells were stimulated with IL-17C and analysed for IL-8 and tumour necrosis factor-α (TNF-α) using qRT-PCR. Control mucosa (n = 5) was immunostained for IL-17A, IL-17C, IL-8, TNF-α and mast cell tryptase and compared with RAU lesions (n = 5) using the mean grey scale value. RESULTS: IL-17C, but no IL-17A, mRNA was found in cultured HOK cells. Components of the heterodimeric IL-17RA/IL-17RE receptor for IL-17C were also highly expressed. Stimulation of HOK with IL-17C increased TNF-α mRNA (P = 0.03; IL-8 increase was not statistically significant). HOK in RAU lesions stained intensively for IL-17C compared to controls (P = 0.006). This was associated with increased epithelial immunostaining of TNF-α (P = 0.04) and IL-8 (P = 0.02). Most of the inflammatory cells which stained for IL-17A in control mucosa and RAU lesions were also mast cell tryptase positive. CONCLUSION: IL-17C is highly expressed in epithelial cells in RAU lesions, where it seems to stimulate oral keratinocytes via IL-17RA/IL-17RE to produce pro-inflammatory cytokines. Human oral epithelial cells are probably important inflammatory cells in RAU.

Recurrent aphthous ulcers--a Toll-like receptor-mediated disease?

BACKGROUND: Recurrent aphthous ulcer (RAU) is characterized by acute and painful inflammatory ulcerations, which heal spontaneously but tend to recur. Many pathogens have been proposed as causative agents, but none has been consistently proven. According to our hypothesis, RAU is an autoinflammatory disorder triggered by pathogen-associated molecular patterns (PAMPs) shared by different pathogenic and commensal microbes. METHODS: PAMP-reactive Toll-like receptors (TLRs) were mapped in oral epithelium in healthy controls compared to RAU. RESULTS: In controls, the superficial epithelium formed a TLR(-), a PAMP non-reactive physical barrier zone, but all TLRs were found deeper in the epithelium, usually restricted to suprabasal and basal cell layers. In RAU, the epithelial TLR polarity was lost: TLRs 1, 2, 5, 7, and 8 were found throughout the epithelium, but also TLRs 4, 6, and 10 extended higher up than normally, whereas TLR-3 was almost lost in RAU. In RAU lesions, connective tissue stroma was heavily infiltrated by TLR(+) inflammatory cells. CONCLUSIONS: Normal TLR architecture prevents inflammatory responses against normal microbes but still contains a deep TLR(+) , PAMP-reactive dormant defense zone. In RAU, the TLR(+), PAMP-reactive zone extends to surface or subsurface exposed to microbial PAMPs. TLR reactivity is further enhanced by recruitment of inflammatory leukocytes forming a new deep line of defense. The organization of the TLR system in healthy mucosa and its changes in RAU are compatible with active pathogenic involvement of TLRs, which together with the typical clinical picture and course suggest that RAU is a TLR-mediated disease.