Introduction IL-17 secreting T cells (Th17h17 and Tc17c17) are subsets of T lymphocytes that have been implicated in autoimmunity, inflammatory disease and provide a link between the innate and adaptive immune responses. High numbers of IL-17-producing T cells are found in close proximity to bile ducts in several liver diseases including primary biliary cirrhosis. IL-17 related cytokines have multiple effects on parenchymal cells in different tissues and may be involved in both effector responses and repair and regeneration. We recently reported increased numbers of liver infiltrating IL-17 secreting CD4 and CD8 T cells in chronic inflammatory liver disease. These cells also secrete IL-21 and IL-22 cytokines reported to promote epithelial repair. In the present study we report the pattern of IL-17, IL-21 and IL-22 receptor expression on hepatic parenchymal cells and demonstrate cell-specific effects of Th17 cytokines on these target cells.
Aim To assess the functional impact of Th17/Tc17 associated cytokines on hepatic parenchymal cells.
Method Primary human cholangiocytes, hepatocytes and sinusoidal endothelial cells were assessed for IL-17, IL-21 and IL-22 receptor expression. The effects of stimulation with recombinant IL-17, IL-21, IL-22, TNF-a or IFN-g alone or in combination were compared on apoptosis, proliferation and cytokine secretion using flow cytometry with annexin or 7-AAD staining and in situ Ki67 staining and measurement of IL-1b, IL-6, IL-23 and TGF-b1 secretion by ELISA.
Results All the parenchymal cell types expressed IL-21R and IL-22R. Th17 and Tc17 cytokines did not cause apoptosis but alone and in combination led to parenchymal cell proliferation. Cholangiocytes and hepatocytes responded best to IL-17, whereas sinusoidal endothelial cells were responsive to IL-22. Cholangiocytes responded to Th17/Tc17 cytokines by secreting high levels of IL-1b, IL-6, IL-23 and TGF-b1 all cytokines that support the survival of Th17 and Tc17 cells.
Conclusion Liver parenchymal cells express IL-17, IL-21 and IL-22 receptors and proliferate in response to Th17/Tc17 cytokines. Cholangiocytes also respond to such cytokines by secreting Th17 polarising cytokines. Thus IL-17 related cytokines secreted by infiltrating lymphocytes may activate the epitheliome to generate a local environment characterised by cholangiocyte proliferation and Th17 cell survival. This response may contribute to the bile duct proliferation and persistent chronic inflammation that characterised many liver diseases.
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