Non-Hematopoietic ?-Arrestin1 Confers Protection Against Experimental Colitis.

ABSTRACT: ?-Arrestins are multifunctional scaffolding proteins that modulate G protein-coupled receptor (GPCR)-dependent and -independent cell signaling pathways in various types of cells. We recently demonstrated that ?-arrestin1 (?-arr1) deficiency strikingly attenuates dextran sodium sulfate (DSS)-induced colitis in mice. Since DSS-induced colitis is in part dependent on gut epithelial injury, we examined the role of ?-arr1 in intestinal epithelial cells (IECs) using a colon epithelial cell line, SW480 cells. Surprisingly, we found that knockdown of ?-arr1 in SW480 cells enhanced epithelial cell death via a caspase-3-dependent process. To understand the in vivo relevance and potential cell type-specific role of ?-arr1 in colitis development, we generated bone marrow chimeras with ?-arr1 deficiency in either the hematopoietic or non-hematopoietic compartment. Reconstituted chimeric mice were then subjected to DSS-induced colitis. Similar to our previous findings, ?-arr1 deficiency in the hematopoietic compartment protected mice from DSS-induced colitis. However, consistent with the role of ?-arr1 in epithelial apoptosis in vitro, non-hematopoietic ?-arr1 deficiency led to an exacerbated colitis phenotype. To further understand signaling mechanisms, we examined the effect of ?-arr1 on TNF-?-mediated NF?B and MAPK pathways. Our results demonstrate that ?-arr1 has a critical role in modulating ERK, JNK and p38 MAPK pathways mediated by TNF-? in IECs. Together, our results show that ?-arr1-dependent signaling in hematopoietic and non-hematopoietic cells differentially regulates colitis pathogenesis and further demonstrates that ?-arr1 in epithelial cells inhibits TNF-?-induced cell death pathways.

SUBMITTER: Lee T 

PROVIDER: S-EPMC4728047 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature