Tuning of interleukin-13 signaling in intestinal epithelial cells via IL-13Ralpha2-induced MAP kinase activation and induction of reactive oxygen species.

摘要

Interleukin-13 (IL-13) is a predominantly T helper 2 (Th2)-derived cytokine that has multiple effects on both haematopoietic and non-haematopoietic cells. Previous findings from our laboratory in a mouse model of colitis, as well as published studies with human ulcerative colitis (UC) tissue, strongly implicate IL-13 as a potential link between UC and colorectal cancer (CRC). We demonstrate two IL-13 receptor chains (IL-13R&agr1 and IL-13R&agr2) are overexpressed on UC- and CRC-derived epithelial cells. Despite similarly elevated receptor chain expression in UC and CRC, IL-13 does not activate the signal transducer and activator 6 (STAT6) or mitogen activated protein kinase (MAPK) pathways in UC, while in colonic tumors only the STAT6 pathway is activated. We discovered that at low concentrations, IL-13R&agr2 signals through the MAPK pathway whereas higher concentrations block the IL-13-induced STAT6- and MAPK-activation. Therefore we conclude IL-13R&agr2 acts as a signaling receptor as well as a decoy receptor, and the strength and character of an IL-13 signal is mediated by the balance between IL- 13R&agr1 and IL-13R&agr2 expression. As the relative expression of IL-13R&agr1 and IL-13R&agr2 modulates one another's transduction pathway, we hypothesized that reactive oxygen 16 species (ROS) might be a common intersection point of signaling pathways emanating from IL-13R&agr1 and IL-13R&agr2 after IL-13 engagement. We demonstrated IL-13 generates ROS via STAT6- and MAPK-dependent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 (NOX-1). IL-13-induced ROS initiates a positive feedback loop to activate signaling through STAT6 and MAPK. IL-13 also stimulates sustained gene expression of two other NADPH oxidases, NOX-4 and DUOX-2, which along with constitutive NOX-1, might facilitate elevated, continuous production of ROS in IL-13 activated intestinal epithelial cells (IEC). We also show that the expression of many of the genes such as trefoil factor 3 (TFF3) and B cell lymphoma extra large (Bcl-xl) essential for IEC biology in wound healing and cell survival are dependent on this intricate and intermingled signal transduction through IL-13 receptors and ROS. Therefore we conclude that IL-13 induced ROS mediates the gene expression pattern in intestinal epithelial cells using an alternate pathway and modulates the wound healing and anti-apoptotic capabilities of the intestinal epithelium.