Abstract
Psoriasis is a chronic immune-mediated inflammatory disease, and a mixed Th1/Th17 cytokine environment plays a critical role in the pathogenesis of psoriasis. Dermal fibroblasts secrete certain cytokines such as IL-6, IL-8, and CXCL-1, contributing to the hyperproliferative state of the epidermis in psoriatic skin. Ultraviolet B (UVB) phototherapy is one of the most commonly used treatments in psoriasis but the influence of UVB on human dermal fibroblasts (HDFs) in psoriasis treatment is not completely understood. We conducted this study to mimic a psoriatic microenvironment in order to investigate and illustrate the combined effects of UVB, IL-17A, and TNF-α on HDFs. The cultured HDFs were obtained from foreskin samples and divided into four groups, as follows: control; IL-17A/TNF-α; UVB; and IL-17A/TNF-α + UVB. Cultured HDFs were irradiated with 30 mJ/cm2 UVB followed by addition of IL-17A/TNF-α and incubated for 24 h. We used real-time quantitative PCR, Western blot, ELISA analysis, and flow cytometry to examine gene and protein expression of related pro-inflammatory cytokines and chemokines and receptors. HDFs produced significant IL-6, IL-8, and CXCL-1 in response to IL-17A/TNF-α stimulation and UVB irradiation but UVB irradiation inhibited IL-17A/TNF-α-induced IL-6, IL-8, and CXCL-1 expression and downregulated the expression of IL-17RA and IL-17RC at both gene and protein levels. Additionally, UVB irradiation induced significant TGF-β1 protein secretion and expression of Smad3 mRNA and protein by HDFs. TGF-β1 significantly induced the expression of Smad3 mRNA and downregulated the IL-17RA and IL-17RC expression on HDFs. UVB irradiation inhibits IL-17A/TNF-α-induced IL-6, IL-8, and CXCL-1 production in HDFs by decreasing the expression of IL-17RA and IL-17RC on fibroblasts through TGF-β1/Smad3 signaling pathway, which reveals a new mechanism of the therapeutic action of UVB on psoriasis.
Highlights
Psoriasis is a chronic immune-mediated inflammatory disease with complex cytokines network and diverse cellular participation, which mainly includes T lymphocytes, keratinocytes, neutrophils, antigen presenting cells, even fibroblasts, and so on
human dermal fibroblasts (HDFs) irradiated with Ultraviolet B (UVB) followed by IL-17A/TNF-α stimulation expressed significantly less IL-6, IL-8, and CXCL-1 mRNA compared with single IL-17A/TNF-α treatment (P < 0.01; Figure 2A), which was confirmed at the protein level (Figures 3A,B)
Western blot did not show significant decrease in IL-6 and CXCL-1 protein in IL-17A/ TNF-α + UVB group compared with IL-17A/TNF-α group, but ELISA analysis confirmed the significant difference of protein secretion
Summary
Psoriasis is a chronic immune-mediated inflammatory disease with complex cytokines network and diverse cellular participation, which mainly includes T lymphocytes, keratinocytes, neutrophils, antigen presenting cells, even fibroblasts, and so on. Dermal fibroblasts can secrete certain cytokines such as IL-6, IL-8, and CXCL-1, which contribute to the hyperproliferative state of the epidermis in psoriatic skin, and these cytokines production in fibroblasts would increase via interaction with neutrophils or normal/malignant epithelial cells, or incubation in the presence of TNF-α or white adipocytessecreted leptin [5,6,7,8]. Psoriasis is a chronic immune-mediated inflammatory disease, and a mixed Th1/Th17 cytokine environment plays a critical role in the pathogenesis of psoriasis. Dermal fibroblasts secrete certain cytokines such as IL-6, IL-8, and CXCL-1, contributing to the hyperproliferative state of the epidermis in psoriatic skin. Ultraviolet B (UVB) phototherapy is one of the most commonly used treatments in psoriasis but the influence of UVB on human dermal fibroblasts (HDFs) in psoriasis treatment is not completely understood
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