Poster Presentation Lorne Infection and Immunity 2014

Interleukin-22 induces the cancer-associated genes carcinoembryonic antigen-related cell adhesion molecule (CEACAM)5 and nicotinamide N-methyltransferase (NNMT) in malignant, but not healthy intestinal cells (#197)

Ina Rudloff 1 2 , Thierry Jarde 3 , Malte Bachmann 2 , Josef M Pfeilschifter 2 , Heiko Muehl 2 , Claudia A Nold-Petry 1 , Helen E Abud 3 , Marcel F Nold 1
  1. Ritchie Centre - Monash Institute of Medical Research, Monash University, Melbourne, Australia
  2. Pharmazentrum Frankfurt, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
  3. Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia

Introduction: IL-22 is predominantly produced by activated leukocytes but, due to limited expression of its receptor complex, acts exclusively on cells of epithelial origin. IL-22 is usually protective in infection-driven inflammation, but can also aggravate autoimmune diseases. Due to the robust activation of STAT3 and subsequent induction of anti-apoptotic proteins, IL-22 promotes proliferation and has been linked to carcinogenesis. NNMT and CEACAM5 are well-established tumour markers for colon carcinoma and are over-expressed in a majority of gastrointestinal malignancies.

Methods: We stimulated DLD-1 colon carcinoma cells with IL-22 and determined changes in genome-wide gene expression by microarray analysis. Newly identified IL-22 responsive genes were then verified by semi-quantitative PCR, RNase protection assays and immunoblots. Organoids generated from small intestines of C57BL/6 mice, which comprise the entire spectrum of primary intestinal cells, were cultured with or without IL-22, and changes in gene expression were determined by real-time PCR.

Results: We identified 27 genes unknown to be regulated by IL-22 (expression changed at least 2-fold) in DLD-1 cells, including inflammation- and cancer-associated genes such as Integrin beta (ITGB)3 (increased 21-fold), NNMT (4-fold), CEACAM5 (3-fold), E74-like factor (ELF)3 (2.5-fold) and B cell lymphoma (BCL)3 (2.5-fold). The induction of NNMT and CEACAM5 was dependent on the IL-22 concentration (5-40 ng/ml) and on the duration of stimulation. Unexpectedly, IL-22 failed to induce NNMT and CEACAM5 in murine intestinal organoids, whereas Mucin1 was upregulated in both experimental settings.

Conclusion: Little is known about the link between IL-22 and carcinogenesis. Here, we show for the first time that IL-22 induces the cancer-associated NNMT and CEACAM5 in carcinoma cell lines, but not in non-neoplastic cells, suggesting that the function of this cytokine depends on the integrity of proliferation control mechanisms in target cells. This finding may represent an important piece in the puzzle of the complex functions of IL-22.