CD137 signaling enhances tight junction resistance in intestinal epithelial cells

Treatment of Caco-2-BBe intestinal epithelial cells (BBe) with TNF-alpha and lymphotoxin-beta (LT-beta) receptor agonists induced the expression of the TNF receptor superfamily gene TNFRSF9/CD137. In the gut, these cytokines are known to be involved in both inflammatory responses and development of organized lymphoid tissues; thus, it was notable that in CD137-deficient mice Peyer's patch M cells lacked transcytosis function. To examine the direct effect of CD137 expression on epithelial cell function independent of other cytokine effects including CD137L triggering, we stably transfected BBe cells to express CD137. CD137 was found at the cell surface as well as the cytoplasm, and confocal microscopy suggested that aggregates of CD137 at the lateral and basolateral surface may be associated with cytoplasmic actin filament termini. Many of the CD137 clusters were colocalized with extracellular fibronectin providing a possible alternative ligand for CD137. Interestingly, we found that CD137-expressing cells showed significantly higher transepithelial electrical resistance (TEER) accompanied by an increase in claudin-4 and decrease in claudin-3 protein expression. By contrast, transfection with a truncated CD137 lacking the cytoplasmic signaling domain did not affect TEER. Finally, CD137-deficient mice showed increased intestinal permeability upon dextran sodium sulfate (DSS) treatment as compared to control mice. Our results suggest that cytokine-induced expression of CD137 may be important in enhancing epithelial barrier function in the presence of intestinal inflammation as well as influencing cytoskeletal organization.