STAT3 and its activators in intestinal defense and mucosal homeostasis

Coordination of innate and adaptive immunity is central to effective mucosal immune defense and homeostasis. The review discusses recent findings on two cytokines, IL-22 and IL-6, and their common signaling pathway, which bridge innate and adaptive immunity in the intestinal tract.

IL-22, a signature product of Th17 cells, is also secreted at functionally significant levels by innate immune cells, especially NKp44/NKp46-expressing natural killer (NK) cells and lymphoid tissue inducer cells after IL-23 stimulation. IL-22 acts primarily on epithelial cells and is overall protective, as its inhibition or loss exacerbates intestinal inflammation. Similarly, IL-6, secreted by macrophages, dendritic cells, epithelial cells, and T cells protects against mucosal damage, but it is also key in the development of Th17 cells, which mediate inflammatory and defensive responses in the intestine. Both cytokines activate STAT3 signaling, whose intestinal activities depend on the specific cell types involved. STAT3 in epithelial and myeloid cells mediates mucosa-protective and anti-inflammatory functions, whereas STAT3 in T cells promotes inflammation.

IL-22 and IL-6 are prime examples of cytokines that coordinate innate and adaptive immune responses in the intestine. They and their common signaling pathway, STAT3 can promote or protect against inflammation indicating that pharmacological manipulation for therapeutic purposes in intestinal inflammatory conditions may present special challenges.