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IL-22-Mediated Tumor Growth Reduction Correlates with Inhibition of ERK1/2 and AKT Phosphorylation and Induction of Cell Cycle Arrest in the G₂-M Phase

Georg F. Weber^1,*, Florian C. Gaertner, Wolfgang Erl, Klaus-Peter Janssen^*, Birgit Blechert, Bernhard Holzmann^*, Heike Weighardt^2,* and Markus Essler^2,

^* Chirurgische Klinik und Poliklinik der Technischen Universität München, Nuklearmedizinische Klinik und Poliklinik der Technischen Universität München, and Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians-Universität München, Munich, Germany

IL-22 is a recently discovered cytokine of the IL-10 family that binds to a class II cytokine receptor composed of IL-22R1 and IL-10R2_c and influences a variety of immune reactions. As IL-22 has also been shown to modulate cell cycle and proliferation mediators such as ERK1/2 and JNK, we studied the role of IL-22 in proliferation, apoptosis, and cell cycle regulation in EMT6 murine breast cancer cells in vitro and in vivo. In this study, we report that murine breast cancer cells express functional IL-22R as indicated by RT-PCR studies, immunoblotting, and STAT3 activation assays. Importantly, IL-22 exposure of EMT6 cells resulted in decreased levels of phosphorylated ERK1/2 and AKT protein kinases, indicating an inhibitory effect of IL-22 on signaling pathways promoting cell proliferation. Furthermore, IL-22 induced a cell cycle arrest of EMT6 cells in the G₂-M phase. IL-22 reduced EMT6 cell numbers and the proliferation rate by 50% as measured by [³H]thymidine incorporation. IL-22 treatment of EMT6 tumor-bearing mice lead to a decreased tumor size and a reduced tumor cell proliferation in vivo, as determined by 3'-deoxy-3'-fluorothymidine-positron emission tomography scans. Interestingly, IL-22 did not induce apoptosis, as determined in annexin V binding assay and caspase-3 activation assay and had no effect on angiogenesis in vivo. In conclusion, our results indicate that IL-22 reduced tumor growth by inhibiting signaling pathways such as ERK1/2 and AKT phosphorylation that promote tumor cell proliferation in EMT6 cells. Therefore, IL-22 may play a role in the control of tumor growth and tumor progression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Georg F. Weber, Department of Surgery, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany. E-mail address: georgfweber{at}web.de

² H.W. and M.E. contributed equally to this work.

³ Abbreviations used in this paper: PI, propidium iodide; DAPI, 4',6'-diamidino-2-phenylindole; FGF, fibroblast growth factor; FLT, 3'-deoxy-3'-fluorothymidine; PET, positron emission tomography; TRITC, tetramethylrhodamine isothiocyanate.

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