P082 Downregulated apelin expression in T cells in the setting of Chronic Colitis

Abstract

Abstract Background APJ is a G protein-coupled receptor and was originally found as an orphan receptor. Isolation of apelin (APL) from the alimentary tract was found to be the endogenous ligand for APJ. It has been reported that APL is upregulated in the colonic tissues of a murine model of acute colitis induced by dextran sodium sulfate (DSS), and thus it may be suggested to be associated with the pathogenesis of inflammatory bowel diseases (IBD) in humans. However, the mechanism and function of APL in the context of IBD are still not understood. Here, we analyzed APL expression in an animal model of chronic colitis to define its function in the pathogenesis of IBD. Methods Each cell type in the colonic tissue, including epithelial cells and lamina propria lymphocytes, were first isolated from wild type C57BL6 mice (WT) to assess APL expression. Next, naïve T cells isolated from WT were adoptively transferred into Rag deficient mice (Rag-/-) to induce chronic colitis, and then APL expression was measured either in the colonic tissue or in the isolated splenic and colonic CD4+ T cells from these T cell-reconstituted Rag-/- to compare with those of WT or Rag-/- without colitis. In addition, WT naïve T cells were differentiated into either Th1, Th2 or Th17 in vitro to analyze APL expression. Finally, the Rag-/- receiving naïve T cells were administered a synthetic APL peptide, APL-13, to assess the severity of colitis. Results Semi-quantitative PCR (qPCR) revealed that CD4+ T cells express relatively higher level of APL compared to other cell types including the epithelial cells in colonic tissue from WT. However, APL expression in the colonic tissues from the Rag-/- induced chronic colitis was unexpectedly downregulated compared to control groups without colitis; this is not consistent with the previous report using acute DSS colitis model. Subsequently, qPCR revealed significantly decreased APL expression in the splenic and colonic T cells from Rag-/- induced colitis compared to that of WT. APL expressions in the effecter T cells in vivo and all of the differentiated T cells in vitro were also significantly downregulated compared to naïve T cells and non-differentiated control T cells, respectively. Given these results, APL-13 was injected into the Rag-/- that underwent T cell reconstitution to antagonize the APL downregulation. This resulted in reduced severity of colitis compared to that of vehicle control-injected group. Conclusion These results suggest that T cells can be one of the major sources of APL in colonic tissues, and APL downregulation in effecter T cells may lead to the development of chronic colitis. In addition, this study also suggests that APL may be a novel therapeutic target for IBD.