title: 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.
abstract: 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 G(2)-M phase. IL-22 reduced EMT6 cell numbers and the proliferation rate by approximately 50% as measured by [(3)H]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.
authors.affiliation: Chirurgische Klinik und Poliklinik der Technischen Universität München, Ismaningerstrasse 22, 81675 Munich, Germany. georgfweber@web.de
authors.forename: Georg F
authors.initials: GF
authors.lastname: Weber
authors.forename: Florian C
authors.initials: FC
authors.lastname: Gaertner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Erl
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
authors.forename: Birgit
authors.initials: B
authors.lastname: Blechert
authors.forename: Bernhard
authors.initials: B
authors.lastname: Holzmann
authors.forename: Heike
authors.initials: H
authors.lastname: Weighardt
authors.forename: Markus
authors.initials: M
authors.lastname: Essler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000097043:Interleukin-22
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D007378:Interleukins; D051058:Oncogene Protein v-akt; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D000097043:Interleukin-22; C415369:interleukin-22 receptor