Abstract

Interleukin-22 (IL-22) is a unique cytokine produced by immune cells and acting exclusively on IL-22 receptor-1 (IL-22-R1) positive epithelial cells. IL-22 plays a central role in epithelial regeneration and contributes to pathogen clearance. In contrast, the proliferation enhancing effects of IL-22 may be used by cancer cells to promote and sustain their growth. This has been shown in genetically modified mouse strains with spontaneous development of colorectal cancer. The cellular sources of IL-22 in tumor tissue are not yet fully identified. In a pilot study with tumor tissue of patients with colorectal cancer, we could identify CD3+CD4+ T cells that produce IL-22. This confirms findings of other groups published in recent years. Peripheral T cells from healthy donors only contained low frequencies of IL-22 producing CD3+CD4+ cells. Upon stimulation, IL-22 induced STAT3 phosphorylation and proliferation of human colon cancer cell lines. In one cell line, we could also show the induction of the cytokines IL-10 and VEGF. IL-22 suppressed IFN-γ- induced synthesis of the chemokine CCL22 in HT29 cells while enhancing TNF-α- induced expression of CCL22 in the same cell line. This indicates differential effects of IL-22 on IFN-γ- and TNF-α-signaling. IFN-γ as well as TNF-α led to IL-22-R1 upregulation in human colon cancer cell lines. In summary, we find evidence that in tumor tissue CD3+ CD4+ T cells produce IL-22. IL-22 acts directly on cells of colorectal cancer cell lines. It enhances their proliferation. IL-22 presumable serves as a mediator in the genesis of colorectal cancer and a potential therapeutic target.