Th17-Derived Cytokines Synergistically Enhance IL-17C Production by the Colonic Epithelium

• Published in: The Journal of immunology (1950) Vol. 209; no. 9; pp. 1768 - 1777
• Main Authors: Swedik, Stephanie M, Madola, Abson, Cruz, Michelle A, Llorens-Bonilla, Braulio J, Levine, Alan D
• Format: Journal Article
• Language: English
• Published: United States 01.11.2022
• Subjects: Cytokines - metabolism; Epithelium - metabolism; Humans; Interleukin-17; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Th17 Cells; Transcription Factor AP-1 - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2200125

Tightly regulated communication between the gastrointestinal epithelium and immune cells in the underlying lamina propria is critical for immune homeostasis and inflammation. IL-17C, produced by epithelial cells after exposure to inflammatory stimuli, facilitates cell-to-cell communication by promoting inflammatory responses in Th17 cells. In this study, we demonstrate that Th17-derived cytokines TNF-α, IL-17A, and IL-22 synergistically enhance IL-17C expression in both human-transformed colonic epithelial cell lines and primary non-inflammatory bowel disease colonic epithelial spheroids. This synergistic expression requires activation of the transcription factor NF-κB downstream of the TNF-α stimulus, evidenced by the reduction of IL-17C expression in the presence of an IκBα inhibitor. IL-17A and IL-22 enhance IL-17C expression through the activation of the transcription factor AP-1 in a p38 MAPK-dependent manner. Colonic spheroids derived from uninvolved epithelial of ulcerative colitis patients stimulated with TNF-α, IL-17A, and IL-22 show muted responses compared with non-inflammatory bowel disease spheroids, and inflamed spheroids yielded more IL-17C expression in the presence of TNF-α, and no response to IL-22 stimulation. Altogether, a role for IL-17C in activating Th17 cells combined with our findings of Th17-derived cytokine-driven synergy in the expression of IL-17C identifies a novel inflammatory amplification loop in the gastrointestinal tract between epithelial cells and Th17 cells.