Interleukin-22 (IL-22), one of the cytokines secreted by T-helper 17 (Th17) 
cells, binds to a class II cytokine receptor containing an IL-22 receptor 1 
(IL-22R1) and IL-10R2 and influences a variety of immune reactions. IL-22 has 
also been shown to modulate cell cycle and proliferation mediators such as 
extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), 
but little is known about the underlying molecular mechanisms of IL-22 in 
tumorigenesis. In this paper, we propose that IL-22 has a crucial role to play 
in controlling epithelial cell proliferation and tumorigenesis in the breast. 
IL-22 increased MAP3K8 phosphorylation through IL-22R1, followed by the 
induction of MEK-ERK, JNK-c-Jun, and STAT3 signaling pathways. Furthermore, 
IL-22-IL-22R1 signaling pathway activated activator protein-1 and HER2 promoter 
activity. In addition, Pin1 was identified as a key positive regulator for the 
phosphorylation-dependent MEK, c-Jun and STAT3 activity induced by IL-22. 
Pin1(-/-) mouse embryonic fibroblasts (MEF) exhibited significantly a decrease 
in IL-22-induced MEK1/2, c-Jun, and STAT3 phosphorylation compared with 
Pin1(+/+) MEF. In addition, a knockdown of Pin1 prevented phosphorylation 
induced by IL-22. The in vivo chorioallantoic membrane assay also showed that 
IL-22 increased tumor formation of JB6 Cl41 cells. Moreover, the knockdown of 
MAP3K8 and Pin1 attenuated tumorigenicity of MCF7 cells. Consistent with these 
observations, IL-22 levels positively correlate with MAP3K8 and Pin1 expression 
in human breast cancer. Overall, our findings point to a critical role for the 
IL-22-induced MAP3K8 signaling pathway in promoting cancer-associated 
inflammation in the tumor microenvironment.