Interleukin-38 promotes skin tumorigenesis via regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment in an IL-1Rrp2-dependent manner

Autor: Hong Zhou, Qi-xiang Zhao, Jia-dong Yu, Cheng-cheng Yue, Yan Hao, Hua-ping Zheng, Jing Hu, Zhen Wang, Jiong Li
Rok vydání: 2021
Předmět:
Zdroj: The Journal of Immunology. 206:22.01-22.01
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.206.supp.22.01
Popis: As the newest member of the IL-1 family, interleukin-38 (IL-38) has strong associations with chronic inflammatory diseases. However, its roles in tumorigenesis and the underlying mechanism remain poorly understood. Here, we demonstrated that IL-38, which was highly expressed in skin, downregulated in human cutaneous squamous cell carcinomas (CSCC) and 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoyl phorbol-13-acetate (TPA) induced mouse skin tumorigenesis. IL-38 keratinocyte-specific knockout mice (IL-38 cKO) dramatically promoted skin tumor formation and their malignant progression. Mechanistically, IL-38 is dispensable for epidermal mutagenesis. IL-38 keratinocyte-specific deletion reduced proliferative gene expression along with epidermal cell proliferation and hyperplasia. Additionally, keratinocyte-specific deletion of IL-38 was associated with reduced secretion of inflammatory cytokines leading to a decreased infiltration of myeloid cells into the local tumor microenvironment, these inflammation-driven tumorigenesis are essential for carcinogenesis process. Furthermore, we first demonstrated that IL-38 activated the c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) signal transduction pathway to promote proliferation and migration of tumor cells and expression of cancer-related inflammatory cytokines in an IL-1 receptor (IL-1R)-related protein 2 (IL-1Rrp2)-dependent manner. Together, our findings highlight the role of IL-38 in the regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment through IL-1Rrp2 /JNK and establish a new defined factor IL-38/ IL-1Rrp2 as therapeutic targets in skin cancer.
Databáze: OpenAIRE