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Abstract
Interleukin-22 (IL-22) is a member of the IL-10 cytokine family that binds to a heterodimeric receptor consisting of IL-22 receptor 1 (IL-22R1) and IL-10R2. IL-22R expression was initially characterized on epithelial cells, and plays an essential role in a number of inflammatory diseases. Recently, a functional receptor was detected on cancer cells such as hepatocarcinoma and lung carcinoma, but its presence was not reported in glioblastoma (GBM). Two GBM cell lines and 10 primary cell lines established from patients undergoing surgery for malignant GBM were used to investigate the expression of IL-22 and IL-22R by using quantitative RT-PCR, western blotting and confocal microscopy studies. The role of IL-22 in proliferation and survival of GBM cell lines was investigated in vitro by BrdU and ELISA cell death assays. We report herein that the two subunits of the IL-22R complex are expressed on human GBM cells. Their activation, depending on exogenous IL-22, induced antiapoptotic effect and cell proliferation. IL-22 treatment of GBM cells resulted in increased levels of phosphorylated Akt, STAT3 signaling protein and its downstream antiapoptotic protein Bcl-xL and decreased level of phosphorylated ERK1/2. In addition, IL-22R subunits were expressed in all the 10 tested primary cell lines established from GBM tumors. Our results showed that IL-22R is expressed on GBM established and primary cell lines. Depending on STAT3, ERK1/2 and PI3K/Akt pathways, IL-22 induced GBM cell survival. These data are consistent with a potential role of IL-22R in tumorigenesis of GBM. Since endogenous IL-22 was not detected in all studied GBM cells, we hypothesize that IL-22R could be activated by immune microenvironmental IL-22 producing cells.
Highlights
Interleukin 22 (IL-22), a member of the IL-10 cytokine family, is produced by several subsets of lymphocytes such as CD4+ T helper 17 (Th17) cells and Th22 cells, CD8+ cytotoxic T cells, natural killer (NK) cells, γδ T cells and lymphoid tissue inducer (LTi)-like cells [1]
The two subunits of the functional IL-22R complex, IL-22 receptor 1 (IL-22R1) and IL-10R2 were detected in the U87MG and the U118MG GBM cell lines both at mRNA (Fig. 1A and 1B) and protein (Fig. 1D and 1E) levels with a higher expression in U87MG cell line
The membranous and cytoplasmic expression of IL-22R1 and IL-10R2 were detected by immunofluorescence in the two GBM cell lines (Fig. 1F), in agreement with the transcriptional and western blot studies, suggesting that GBM cancer cell lines have the ability to respond to IL-22 stimulation
Summary
Interleukin 22 (IL-22), a member of the IL-10 cytokine family, is produced by several subsets of lymphocytes such as CD4+ T helper 17 (Th17) cells (able to produce IL-17A and IL17F) and Th22 cells, CD8+ cytotoxic T cells, natural killer (NK) cells, γδ T cells and lymphoid tissue inducer (LTi)-like cells [1]. Binding of IL-22 to its receptor activates the Janus kinase 1 (JAK1), followed by the signal transducers and activators of transcription protein 3 (STAT3) and STAT5 pathways [13, 14]. IL-22 activates the MAP kinase pathways such as the extracellular signal regulated kinase 1/2 (ERK1/2), mitogen activated protein kinases (MAPK) like c-Jun N-terminal kinase (JNK) and p38 [1, 8, 13]. IL-22 activates the phosphatidylinositide 3-Kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway [8, 15, 16]
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