IL-22による口腔扁平上皮癌におけるSTAT3シグナル伝達経路について

Cytokines or cytokine-related mediators influence the cellular behavior of malignant tumors. Interleukin-22 (IL-22) is a member of the IL-10 family. Its main targets are epithelial cells, but not immune cells. The objectives of this study were to examine IL-22 signal transduction in oral squamous cell carcinoma (OSCC) cells. RT-PCR showed that human OSCC cells, MISK81-5 and HSC-3 cells, expressed IL-22 receptor chains. Immunoblotting showed that IL-22 induced a transient tyrosine phosphorylation of STAT3 (pY705-STAT3) in MISK81-5 cells after IL-22 stimulation. The change in the serine phosphorylation of STAT3 was subtle during the examination periods. Meanwhile pY705-STAT3 activation in HSC-3 cells was undetectable after IL-22 stimulation. The immunocytochemistry demonstrated that IL-22 induced translocation of phosphorylated STAT3 into the nucleus of MISK81-5 cells. IL-22 temporarily up-regulated the expression of anti-apoptotic and mitogenic genes such as Bcl-xL, survivin and c-Myc as well as SOCS3. IL-22 transiently activated ERK1/2 and induced a delayed phosphorylation of p38 MAP kinase. ERK1/2 phosphorylation was decreased below the control level after 30 min. IL-22 negligibly involved activation of NF-κB as detected by using MISK81-5 cells stably transfected with pGL4.26[luc2/minP/Hygro] encompassed four tandem copies of the NF-κB consensus sequence. MISK81-5 cells treated with IL-22 showed mild cellular proliferation and down-regulation of the keratinocyte differentiation-related genes in comparison to unstimulated cells. IL-22 also increased MMP-2 protein in MISK81-5 cells, but not MMP-9. An unexpected finding was that the phosphorylation of STAT3 was attenuated in MISK81-5 cells pretreated with AG490, a specific JAK2 inhibitor, even after IL-22stimulation. The mechanism remained unclear. These results indicated that IL-22 differentially activated the STAT3 signaling system depending on the type of OSCC. IL-22 may play roles in the tumor growth, cell differentiation and progression through the activation of the STAT3 pathway. The blockade of JAK/STAT signals may provide a novel therapeutic strategy for OSCC.List of Submitted Paper and Presentation / List of Contents / LIST OF ABBREVIATION / Abstract / Introduction / Materials and Methods / Results / Discussion / ACKNOWLEDGEMENTS / REFERENCE