IL-23 promotes growth and proliferation in human squamous cell carcinoma of the oral cavity.
Interleukin (IL)-23 is a heterodimeric cytokine, comprising IL-12p40 and the cloned IL-23-specific p19 subunit, was identified as a cancer-associated cytokine in a recent study. Like IL-12, IL-23 is expressed predominantly by activated dendritic cells and phagocytic cells. These cytokines antagonistically regulate local inflammatory responses in the tumor microenvironment and infiltration by intraepithelial lymphocytes. We have previously demonstrated the expression of IL-23 and its receptors in human oral squamous cell carcinoma (HOSCC) cell lines and tissue. Hence, this study investigated whether IL-23 has a role in the growth and proliferation of oral cancer cells by examining the expression kinetics of IL-23 and NF-kappaB activity, in vitro and in vivo. IL-23, which constitutively expressed in oral cancer, was enhanced by TNF-alpha and IL-23. IL-23 promotes cell proliferation in oral cancer and enhances the transport of nuclear factor-kappaB (NF-kappaB p65, RelA) to the nucleus in HSC-3 cells. Furthermore, luciferase reporter assay showed that IL-23 strongly induces RelA activity, and confirmed this finding by knockdown of IL-23 using RNA interference. Although RelA activity was down-regulated by anti-human IL-23p19 polyclonal antibody, used to neutralize the activity of IL-23, apoptosis was not induced. Immunohistochemistry revealed a weak IL-23 immunoreactivity in the cytoplasm of inflammatory infiltrating cells and in the cancer cells derived from 14 of 40 cases (35%) of oral SCC. In contrast, strong RelA immunoreactivity was observed in 30 of 40 cases of SCC (75%), especially consistent with IL-23 positive cells in SCC tissues. These data suggest that IL-23 up-regulates the growth and cell proliferation of oral cancer by promoting the nuclear transactivation of RelA.