CXCL1 Inhibition Regulates UVB-Induced Skin Inflammation and Tumorigenesis in Xpa-Deficient Mice.

Xeroderma pigmentosum complementation group A is a hereditary disease characterized by early onset of skin cancers and freckle-like pigmented maculae in sun-exposed sites. Although the etiology of the predisposition to UVR-induced skin tumors in xeroderma pigmentosum complementation group A is well investigated as a repair deficiency in UVR-induced DNA damage, the mechanism of exaggerated sunburn in patients with xeroderma pigmentosum complementation group A and whether UVR-induced inflammation relates to a skin tumor-prone phenotype remains to be elucidated. Using gene profiling of xeroderma pigmentosum complementation group A model mice, Xpa-deficient mice, we found that expression of CXCL1 in the skin and blood of Xpa-deficient mice increased significantly after UVB exposure over even a limited area compared with that of wild-type mice. We administered CXCL1 neutralizing antibody or the antioxidant agent, N-acetylcysteine, to Xpa-deficient mice after UVB irradiation and found significant suppression of blood levels of CXCL1, ear swelling and erythema, the hallmarks of inflammation and neutrophil chemotaxis. Xpa-deficient mice treated with chronic UVB exposure plus administration of CXCL1 neutralizing antibody or N-acetylcysteine yielded many fewer skin tumors compared with the control group. This indicates that the UVB-induced strong inflammatory response of Xpa-deficient mice plays a role in skin tumor development, which could be suppressed by regulating chemokines such as CXCL1.

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