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Cxcl1 antagonist on UVB-induced skin inflammation leading to inhibitory effects on photo-skin tumorigensis in Xeroderma pigmentosum type A deficient mice

ABSTRACT: Xeroderma pigmentosum type A (XP-A) is a hereditary disease characterized by early onset of skin cancers development by ultraviolet (UV) exposure. Although etiology of susceptible to skin tumor of XP-A is well investigated as a repair deficiency by UV-induced DNA damage, the mechanism of unusual strong and prolonged skin inflammation caused by UV in XP-A and whether UV-induced inflammatory response relates to skin tumor-prone phenotype remains to be elucidated. Among up-regulated inflammatory response related genes in Xpa mice compared with wild-type by gene profiling study, Cxcl1 in Xpa mice was significantly different from wild-type and blood level of Cxcl1 was increased with UVB exposed on even small area of skin in Xpa mice. We administered Cxcl1 neutralizing antibody or antioxidant agent n-acetylcysteine for Xpa mice after UVB irradiation, showing that blood levels of Cxcl1, ear swelling and skin redness as an inflammatory response were significantly suppressed. Xpa mice with chronic UVB exposure and Cxcl1 neutralizing antibody or n-acetylcysteine administered Xpa mice yields much less skin tumors compared with control group. Those results indicate that highly inflammatory response of Xpa mice by UVB plays a role of skin tumor development that could be suppressed by chemokine as Cxcl1 through antioxidant mechanism.

ORGANISM(S): Mus musculus

PROVIDER: GSE86093 | GEO | 2017/06/01

SECONDARY ACCESSION(S): PRJNA340244

REPOSITORIES: GEO

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Project description:UV irradiation is a major environmental effector of skin damage and aging. Elevated levels of glycosaminoglycans (GAGs), as measured by Hale’s stain, are seen following cutaneous photodamage. Preliminary data from our lab indicates that this is a complex response involving differential regulation of both GAGs and proteoglycans. Recently, different GAG species have been shown to have distinct effects on the recruitment and activation of immune cells and stimulation of cytokine production (Taylor and Gallo, FASEB, 2006; 20: 9-22). We speculate that the elevated GAGs and proteoglycans observed after ultraviolet B (UVB) irradiation are involved in the inflammatory and healing responses to photodamage. Chondroitin sulfate synthases (CSSs) are not increased by UVB in mice or in cultured human fibroblasts. To determine whether genomic upregulation of CSSs is responsible for the post-UVB CS increase, we measured the dermal expression of CSS1 and CSS3 mRNA in C57Bl6 mice after 5 days of UV-B exposure. Irradiation caused no change in either CSS1 or CSS3 mRNA expression. We also studied CSS RNA expression in cultured human fibroblasts. We compared control cells to cells treated with 30 mJ/cm2 UVB, cells treated with 1 ng/mL IL-1α, and cells co-stimulated with UVB and IL-1α. In vivo, UV-B induces IL-1α production by keratinocytes and inflammatory cells, and this IL-1α interacts with fibroblasts. Co-stimulation with IL-1α + UVB induces TNF-α production by the fibroblasts, mirroring the in vivo interaction. CSS1 mRNA was suppressed 60% and CSS3 mRNA expression dropped 87% relative to sham at 24 hours post-treatment (p<0.001, Dunnet q’). Since CS is not upregulated by its synthases, we postulated an alternative mode of induction whereby one or more CS proteoglycans are transcriptionally increased and bind more CS in the dermis. We used the N-13 goat monoclonal anti-serglycin antibody to visualize changes in cutaneous serglycin content following acute UV-B exposure. Serglycin is one example of CS-binding dermal proteoglycans that is induced by UVB, and there are likely others. Diffuse upper-dermal serglycin staining, like upper-dermal CS, was induced continuously at 24, 48, and 72 hours after irradiation. Serglycin-expressing inflammatory cells are recruited to the dermis following irradiation, peaking at 48 hours post-exposure. A statistically significant 1.70 fold increase in serglycin mRNA was measured in cultured human fibroblasts 6 hours after co-stimulation with UVB and IL-1α. Realtime PCR also revealed a significant 2.04 fold upregulation at 24 hours after co-stimulation, and serglycin was increased 4.63 times 6 hours after Il-1α treatment alone.

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Cxcl1 antagonist on UVB-induced skin inflammation leading to inhibitory effects on photo-skin tumorigensis in Xeroderma pigmentosum type A deficient mice

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