Possible role of epiregulin from dermal fibroblasts in the keratinocyte hyperproliferation of psoriasis.
Psoriasis, an immune-mediated inflammatory disease, is characterized by keratinocyte hyperproliferation. Tumor necrosis factor (TNF)-α, interleukin (IL)-23, and IL-17A play critical roles in the pathogenesis of psoriasis. IL-17A secreted by T-helper 17 acts more directly against keratinocytes than TNF-α or IL-23 do. Regarding the receptors of cytokines, fibroblasts also express receptors against IL-17A and TNF-α, and induce the production of growth factors. Epiregulin (EREG), an epidermal growth factor receptor ligand, is produced by both keratinocytes and fibroblasts. EREG enhances keratinocyte proliferation and differentiation. We hypothesized that fibroblasts stimulated with IL-17A and/or TNF-α may play a role in epidermal hyperproliferation through the production of epidermal growth factors in psoriasis. The mRNA expression of EREG was found to be significantly upregulated by co-stimulation with IL-17A and TNF-α (mean, 49.2-fold). Furthermore, the stimulation with TNF-α alone, but not IL-17A alone, induced significant increases. Immunofluorescent staining demonstrated that the protein expression level of EREG was also increased in fibroblasts stimulated with these cytokines. Stimulation with EREG significantly enhanced keratinocyte proliferation in vitro. In human psoriatic patients' skin, immunofluorescence staining of EREG showed significantly high intensity in the dermis of lesional skin. In conclusion, cytokine stimulation with TNF-α and IL-17A induces the overexpression of EREG from dermal fibroblasts in the lesional skin of psoriasis, and plays a role in epidermal hyperproliferation.
['Iwata|Hiroaki|H|https://orcid.org/0000-0002-8781-2735', 'Haga|Naoya|N|https://orcid.org/0000-0002-2749-3795', 'Ujiie|Hideyuki|H|https://orcid.org/0000-0002-3489-5418']
D049109:Cell Proliferation D066260:Epiregulin D005347:Fibroblasts D006801:Humans D015603:Keratinocytes D011565:Psoriasis D012867:Skin
epiregulin fibroblast psoriasis growth factor acanthosis