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

J Immunol. 2006 Dec 1;177(11):8266-72. doi: 10.4049/jimmunol.177.11.8266.

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.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Blotting, Western
  • Breast Neoplasms / metabolism*
  • Cell Cycle / physiology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression
  • Interleukin-22
  • Interleukins / metabolism*
  • Mice
  • Oncogene Protein v-akt / metabolism*
  • Phosphorylation
  • RNA, Messenger / analysis
  • Receptors, Interleukin / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*

Substances

  • Interleukins
  • RNA, Messenger
  • Receptors, Interleukin
  • interleukin-22 receptor
  • Oncogene Protein v-akt
  • Extracellular Signal-Regulated MAP Kinases