Abstract
The interleukin (IL)-20 subfamily of cytokines consists of IL-19, IL-20, IL-22, IL-24, and IL-26, and the expression of IL-20, IL-22, and IL-24 is reported to be higher in the colon of patients with ulcerative colitis. Although the receptors for these cytokines are highly expressed in the colon epithelium, their effects on epithelial renewal are not clearly understood. This study evaluated the effects of IL-20, IL-22, and IL-24 in epithelial renewal using the LS174T human colon cancer epithelial cell line. LS174T cells were treated with IL-20, IL-22, and IL-24 (25, 50, and 100 ng/mL) and a live-cell imaging system was used to evaluate the effects on cell proliferation. Following treatment, the signaling pathways contributing to cell proliferation were investigated through Western blotting in LS174T cells and downstream transcriptional changes through qRT-PCR in LS174T cells, and RNA-Seq in primary murine intestinal epithelial cells. Our results demonstrated that only IL-22 promoted LS174T cell proliferation, mediated via extracellular-signal-regulated kinase (ERK)1/2-mediated downstream regulation of p90RSK, c-Jun, and transcriptional changes of TRIM15 and STOM. IL-22 also promoted expression of ERK1/2-independent genes such as DDR2, LCN2, and LRG1, which are known to be involved in cell proliferation and migration. This study suggests that IL-22 induces cell proliferation in highly proliferative cells such as intestinal epithelial cells.
Highlights
The gastrointestinal tract is the largest organ that is continuously exposed to dietary antigens and commensal microbiota
This rapid and dynamic turnover of the epithelium is critically regulated by multiple factors in the environment of the stem cell/transit-amplifying cell niche including hormones, cytokines, and chemokines secreted from the immune cells and peripheral organs [17]
It has been found that the expression levels of IL-20, IL-22, and IL-24 are higher in the colon of patients with ulcerative colitis [4] but that their roles in colonic epithelial renewal are not clearly understood
Summary
The gastrointestinal tract is the largest organ that is continuously exposed to dietary antigens and commensal microbiota. The interleukin (IL)-20 subfamily of cytokines belongs to the large IL-10 family and consists of IL-19, IL-20, IL-22, IL-24, and IL-26 These cytokines are primarily produced by leukocytes but preferentially act on non-hematopoietic cells, epithelial cells [4]. There is data demonstrating that IL-20, IL-22, and IL-24 can act on epithelial cells and modulate their function These cytokines act through the heterodimeric receptor complexes of IL-20RA/IL-20RB and IL-22RA/IL-20RB (IL-20 and IL-24), and IL-22RA/IL-10RB (IL-22). The cytokines can bind with an individual subunit, binding with the heterodimeric complex is necessary for appropriate signal transduction [4].
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