Interleukin-21
positive regulation of cytokine production
Il-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease.
<h4>Background</h4>Interleukin-21 (IL-21) is involved in T and NK cell activation and effector response and promotes Th17 cell differentiation. Here we investigated IL-21 receptor (IL-21R) expression in inflamed mucosa of inflammatory bowel disease (IBD) and evaluated its role in the induction of NK cell cytotoxicity and activation as well as Th17 differentiation.<h4>Methods</h4>Expression of IL-21R was performed by immunohistochemistry and flow cytometry. NK cell cytotoxicity was detected by a standard (51)Cr-release assay. Cytokine levels were analyzed by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (PCR).<h4>Results</h4>IL-21R-positive cells were significantly increased in inflamed mucosa of IBD compared with controls, and mainly expressed in freshly isolated peripheral blood (PB)- and lamina propria (LP)-CD4(+), CD8(+) T, B, and NK cells. PB-NK cells from IBD patients produced higher levels of interferon gamma (IFN-gamma) and tumor necrosis factor (TNF) than controls when stimulated with immobilized human IgG and IL-21. IL-21-primed IBD NK cells showed a more potent antitumor cytotoxicity to NK-sensitive K562 cells than controls. Moreover, PB-T and LP-T cells from IBD patients produced large amounts of proinflammatory cytokines (e.g., TNF, IFN-gamma) than controls when stimulated with IL-21 and anti-CD3. Importantly, IL-21 facilitated IBD CD4(+) T cell to differentiate into Th17 cells, characterized by increased expression of IL-17A and ROR gamma t.<h4>Conclusions</h4>IL-21 enhances IBD NK cell cytotoxic response, triggers T cells to produce proinflammatory cytokines, and induces IBD CD4(+) T cells to differentiate into Th17 cells, suggesting that IL-21 is involved in the pathogenesis of IBD and that blocking IL-21R signaling may have a therapeutic potential in IBD.