Lymphatic Dysfunction Exacerbates Cutaneous Tumorigenesis and Psoriasis-Like Skin Inflammation through Accumulation of Inflammatory Cytokines

Abstract

Lymphatic transport plays an important role in coordinating local immune responses. However, the biologic effects of impaired lymphatic flow invivo are not fully understood. In this study, we investigated the roles ofthe lymphatic system in skin carcinogenesis and psoriasis-like inflammation using k-cyclin transgenic (kCYC+/-) mice, which demonstrate severe lymphatic dysfunction. kCYC+/- mice showed augmented tumor growth in the two-stage skin carcinogenesis model and severe clinical scores in imiquimod-induced psoriasis-like skin inflammation compared with wild-type mice. Although mRNA levels of inflammatory cytokines in skin after topical application of 12-O-tetradecanoylphorbol-13-acetate or imiquimod were comparable between kCYC+/- and wild-type mice, protein levels of inflammatory cytokines, such as IL-17A, IL-22, and IL-23, were significantly upregulated in kCYC+/- mice in both models. Consistently, signal transducer and activator of transcription 3 pathway and NF-κB signaling were augmented in epidermal keratinocytes in kCYC+/- mice. These results suggest that lymphatic dysfunction in kCYC+/- mice caused accumulation of inflammatory cytokines, leading to the exacerbation of two-stage skin carcinogenesis and imiquimod-induced psoriasis-like skin inflammation. These findings add insight into the clinical problems of secondary malignancies and inflammatory dermatoses that may occur with extremity lymphedema.